Novel modulators of the sigma-2 receptor and their method of use

ABSTRACT

Pharmaceutical compositions of the invention comprise functionalized lactone derivatives having a disease-modifying action in the treatment of diseases associated with dysregulation of sigma-2 receptor activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application62/474,277, filed Mar. 21, 2017, which is incorporated herein byreference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under grant numberHHSN-271-2008-00025-C awarded by the National Institute of Mental Healthand grant number 1R41AG052249-01 awarded by the National Institute onAging. The government has certain rights in the invention.

FIELD OF INVENTION

Embodiments of the invention are directed to novel compounds useful assigma-2 receptor binders and their method of use. Embodiments arefurther directed to a novel chemotype useful for the treatment diseasesthat are associated with dysregulation of sigma-2 receptor activity.

BACKGROUND OF THE INVENTION

The sigma-1 and sigma-2 receptors were first identified in themid-1970's based on their interaction with radioligands. In 1976, astudy of the physiological properties of (±)-SKF-10,047(N-allylnormetazocine) and it structurally related benzomorphananalogues, morphine and ketazocine, in the chronic spinal dog modelidentified three receptor sub-types, the μ-opioid receptor, the κ-opioidreceptor, and the σ-receptor (sigma receptor) (Martin, W. R.; Eades, C.G.; Thompson, J. A.; Huppler, R. E.; Gilbert, P. E. The effects ofmorphine- and nalorphine-like drugs in the nondependent andmorphine-dependent chronic spinal dog. J. Pharmacol. Exp. Ther. 1976,197, 517-532). It subsequently determined that (−)-SKF-10,047 binds tothe μ-opioid receptor and the κ-opioid receptor, while (+)-SKF-10,047selectively to the 6-receptor (sigma receptor), although the truefunction of the 6-receptor remained unknown (Matsumoto, R. R. SigmaReceptors: Historical Perspective and Background. In Sigma Receptors:Chemistry, Cell Biology and Clinical Implications; Matsumoto, R. R.,Bowen, W. D., Su, T.-P., Eds.; Springer Science: New York, N.Y., 2007;pp 1-23. Collier, T. L.; Waterhouse, R. N.; Kassiou, M. Imaging sigmareceptors: applications in drug development. Curr. Pharm. Des. 2007, 13,51-72.) The availability of the σ-receptor selective radioligand[³H]o-ditolylguanidine (DTG) facilitated more detailed binding studiesof ligand for the σ-receptor, and eventually lead to the identificationof two distinct subtypes, the σ₁-receptor and the σ₂-receptor(Hellewell, S. B.; Bowen, W. D. A sigma-like binding site in ratpheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphansand lower molecular weight suggest a different sigma receptor form fromthat of guinea pig brain. Brain Res. 1990, 527, 244-253.) Although theexact structure of the σ₂-receptor is unknown, recent studies havephotoaffinity labeling studies have suggested that the σ₂-receptor issynonymous with the progesterone receptor membrane component-1 (PGRMC1)(Xu, J. et al. Identification of the PGRMC1 protein complex as theputative sigma-2 receptor binding site. Nat. Commun. 2, 380 (2011).

The therapeutic utility of compounds capable of binding to theσ₂-receptor or modulating activity of the σ₂-receptor has also beenexplored. It has recently been discovered, for example, that compoundscapable of binding to the σ₂-receptor can prevent the binding of betaamyloid protein (A3) oligomers to neurons, thereby preventing downstreamsynaptotoxicity. This aspect of σ₂-receptor binders provides anopportunity for the application of σ₂-receptor binders as treatment forAlzheimer's disease, mild cognitive impairments, and memory disorders.It has further been demonstrated that compounds capable of binding tothe σ₂-receptor can displace beta amyloid protein (Aβ) oligomers fromneurons, thereby preventing downstream synaptotoxicity. This aspect ofσ₂-receptor binders also provides an opportunity for the application ofσ₂-receptor binders as treatment for Alzheimer's disease, mild cognitiveimpairments, and memory disorders (Izzo, N. J. et al. Alzheimer'stherapeutics targeting amyloid Beta 1-42 oligomers I: abeta 42 oligomerbinding to specific neuronal receptors is displaced by drug candidatesthat improve cognitive deficits. PLoS One 9, e111898 (2014). Izzo, N. J.et al. Alzheimer's Therapeutics Targeting Amyloid Beta 1-42 OligomersII: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding andSynaptotoxicity. PLoS One 9, e111899 (2014).

Separately, it is has demonstrated that expression of the σ₂-receptor iselevated in tumor cells as compared with normal cells. Cancer cells inwhich overexpression of the σ₂-receptor occurs, but is not limited to,pancreatic cancer, lung cancer, breast cancer, melanoma, prostatecancer, and ovarian cancer. It has been further discovered thatcompounds capable of binding to the σ₂-receptor modulate its activityand induce cancer cell death. As such, the σ₂-receptor is a viabletarget for the identification of anti-cancer agents, and compoundscapable of binding to the σ₂-receptor represent an opportunity todevelop new anti-cancer agents.

The dysregulation of sigma-2 receptor activity has also been implactedin a number of neuropsychiatric disorders including but not limited togeneralized anxiety disorder, social anxiety disorder, panic disorder,agoraphobia, obsessive-compulsive disorder post-traumatic stressdisorder, depression, bipolar disorder, anorexia nervosa, bulimianervosa, substance use disorders, and schizophrenia (Guo, L.; Zhen, X.Simga-2 Receptor ligands: Neurobiological effects. Current MedicincalChemistry, 2015, 22, 8, 989-1003. Skuza, G. Pharmacology of sigma (σ)receptor ligands from a behavioral perspective. Current PharmaceuticalDesign, 2012, 18, 7, 863-874.). As such, the σ₂-receptor is a viabletarget for the treatment of neuropsychiatric disorders including but notlimited to generalized anxiety disorder, social anxiety disorder, panicdisorder, agoraphobia, obsessive-compulsive disorder post-traumaticstress disorder, depression, bipolar disorder, anorexia nervosa, bulimianervosa, substance use disorders, and schizophrenia. Compounds that bindto the σ₂-receptor that are capable of modulating σ₂-receptor representan opportunity to identify new treatments for a number ofneuropsychiatric disorders including but not limited to generalizedanxiety disorder, social anxiety disorder, panic disorder, agoraphobia,obsessive-compulsive disorder post-traumatic stress disorder,depression, bipolar disorder, anorexia nervosa, bulimia nervosa,substance use disorders, and schizophrenia.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed toward novel sigma-2 receptor binders,compounds of formula (I),

including hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein:

A is selected from a group consisting of

n is 1, 2, or 3;

R^(1a) and R^(1b) are each independently selected from the groupconsisting of hydrogen, C₁₋₆ linear alkyl, and C₁₋₆ branched alkyl, orR^(1a) and R^(1b) may be taken together with the atom to which they arebound to form a ring having from 3 to 7 ring atoms;

R² is selected from a group consisting of a benzene ring that isoptionally substituted with 0 to 3 R⁴ groups that are not hydrogen, a4-pyridine ring that is optionally substituted with 0 to 2 R⁵ groupsthat are not hydrogen, a 3-pyridine ring that is optionally substitutedwith 0 to 2 R⁵ groups that are not hydrogen, and a 2-pyridine ring thatis optionally substituted with 0 to 2 R⁵ groups that are not hydrogen;

R³ is selected from a group consisting of a benzene ring that isoptionally substituted with 0 to 3 R⁴ groups that are not hydrogen, a4-pyridine ring that is optionally substituted with 0 to 2 R⁵ groupsthat are not hydrogen, a 3-pyridine ring that is optionally substitutedwith 0 to 2 R⁵ groups that are not hydrogen, and a 2-pyridine ring thatis optionally substituted with 0 to 2 R⁵ groups that are not hydrogen;

R⁴ is at each occurrence independently selected from the groupconsisting of hydrogen, OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branchedalkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R⁸, NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b);

the terms R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) may be used todesignate individual R⁴ groups on a benzene ring;

R⁵ is at each occurrence independently selected from the groupconsisting of hydrogen, OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branchedalkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹, and NR^(9a)SO₂NR^(12a)R^(12b);

the terms R^(5a), R^(5b), R^(5c), and R^(5d) may be used to designateindividual R⁵ groups on a pyridine ring;

R⁶ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R⁷ is at each occurrence independently selected from the groupconsisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(8a) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(8b) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(9a) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(9b) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(9a) and R^(9b) may be taken together with the atom to which they arebound to form a ring having from 3 to 7 ring atoms optionally containingan oxygen;

R¹⁰ is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R¹¹ is at each occurrence independently selected from the groupconsisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(12a) is at each occurrence independently selected from the groupconsisting of hydrogen, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl; and

R^(12b) is at each occurrence independently selected from the groupconsisting of hydrogen, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl.

The present invention further relates to compositions comprising: aneffective amount of one or more compounds according to the presentinvention and an excipient.

The present invention also relates to a method for treating orpreventing diseases that involve dysregulation of sigma-2 receptoractivity, for example neuropsychiatric disorders such as generalizedanxiety disorder, social anxiety disorder, panic disorder, agoraphobia,obsessive-compulsive disorder post-traumatic stress disorder,depression, bipolar disorder, anorexia nervosa, bulimia nervosa,substance use disorders, schizophrenia, Alzheimer's disease, mildcognitive impairment, and memory disorders, as well as cancer, forexample pancreatic cancer, lung cancer, breast cancer, melanoma,prostate cancer, and ovarian cancer said method comprising administeringto a subject an effective amount of a compound or composition accordingto the present invention.

The present invention yet further relates to a method for treating orpreventing diseases that involve dysregulation of sigma-2 receptoractivity, for example neuropsychiatric disorders such as generalizedanxiety disorder, social anxiety disorder, panic disorder, agoraphobia,obsessive-compulsive disorder post-traumatic stress disorder,depression, bipolar disorder, anorexia nervosa, bulimia nervosa,substance use disorders, schizophrenia, Alzheimer's disease, mildcognitive impairment, and memory disorders, as well as cancer, forexample pancreatic cancer, lung cancer, breast cancer, melanoma,prostate cancer, and ovarian cancer wherein said method comprisesadministering to a subject a composition comprising an effective amountof one or more compounds according to the present invention and anexcipient.

The present invention yet further relates to a method for treating orpreventing diseases that involve overexpression of the sigma-2 receptorsuch as cancer, for example pancreatic cancer, lung cancer, breastcancer, melanoma, prostate cancer, and ovarian cancer said methodcomprising administering to a subject an effective amount of a compoundor composition according to the present invention.

The present invention yet further relates to a method for treating orpreventing diseases that involve overexpression of the sigma-2 receptorsuch as cancer, for example pancreatic cancer, lung cancer, breastcancer, melanoma, prostate cancer, and ovarian cancer wherein saidmethod comprises administering to a subject a composition comprising aneffective amount of one or more compounds according to the presentinvention and an excipient.

The present invention also relates to a method for treating orpreventing disease or conditions associated with dysregulation ofsigma-2 receptor activity. Said methods comprise administering to asubject an effective amount of a compound or composition according tothe present invention.

The present invention yet further relates to a method for treating orpreventing disease or conditions associated with dysregulation ofsigma-2 receptor activity, wherein said method comprises administeringto a subject a composition comprising an effective amount of one or morecompounds according to the present invention and an excipient.

The present invention further relates to a process for preparing thesigma-2 receptor binders modulators of the present invention.

These and other objects, features, and advantages will become apparentto those of ordinary skill in the art from a reading of the followingdetailed description and the appended claims. All percentages, ratiosand proportions herein are by weight, unless otherwise specified. Alltemperatures are in degrees Celsius (° C.) unless otherwise specified.All documents cited are in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

There is evidence that suggests a role for the sigma-2 receptor in anumber of disease states including, but not limited to neuropsychiatricdisorders such as generalized anxiety disorder, social anxiety disorder,panic disorder, agoraphobia, obsessive-compulsive disorderpost-traumatic stress disorder, depression, bipolar disorder, anorexianervosa, bulimia nervosa, substance use disorders, and schizophrenia,cancers such as pancreatic cancer, lung cancer, breast cancer, melanoma,prostate cancer, and ovarian cancer, as well as Alzheimer's disease,mild cognitive impairments, and memory disorders. Sigma-2 receptoractivity modulators are likely to have a beneficial effect on patientssuffering from these diseases and disorders. The disorders in whichSigma-2 receptor dysregulation plays a role and modulation of Sigma-2receptor receptor activity by a therapeutic agent may be a viableapproach to therapeutic relief include, but are not limited to,neuropsychiatric disorders such as generalized anxiety disorder, socialanxiety disorder, panic disorder, agoraphobia, obsessive-compulsivedisorder post-traumatic stress disorder, depression, bipolar disorder,anorexia nervosa, bulimia nervosa, substance use disorders, andschizophrenia, cancers such as pancreatic cancer, lung cancer, breastcancer, melanoma, prostate cancer, and ovarian cancer, as well asAlzheimer's disease, mild cognitive impairments, and memory disorders.

There is a long felt need for new Sigma-2 receptor binders and Sigma-2receptor activity modulators that will provide therapeutic relief frompatients suffering from diseases associated with dysregulation of theSigma-2 receptor. The invention addresses the need to identify novelSigma-2 receptor binders and Sigma-2 receptor activity modulatorscapable to treating disease associated with dysregulation of Sigma-2receptor activity. The present invention addresses the need to developnew therapeutic agents for the treatment and prevention ofneuropsychiatric disorders such as generalized anxiety disorder, socialanxiety disorder, panic disorder, agoraphobia, obsessive-compulsivedisorder post-traumatic stress disorder, depression, bipolar disorder,anorexia nervosa, bulimia nervosa, substance use disorders, andschizophrenia, cancers such as pancreatic cancer, lung cancer, breastcancer, melanoma, prostate cancer, and ovarian cancer, as well asAlzheimer's disease, mild cognitive impairments, and memory disorders.

The Sigma-2 receptor binders and Sigma-2 receptor activity modulators ofthe present invention are capable of treating and preventing diseasesassociated with dysregulation of the sigma-2 receptor, for exampleneuropsychiatric disorders such as generalized anxiety disorder, socialanxiety disorder, panic disorder, agoraphobia, obsessive-compulsivedisorder post-traumatic stress disorder, depression, bipolar disorder,anorexia nervosa, bulimia nervosa, substance use disorders, andschizophrenia, cancers such as pancreatic cancer, lung cancer, breastcancer, melanoma, prostate cancer, and ovarian cancer, as well asAlzheimer's disease, mild cognitive impairments, and memory disorders.Without wishing to be limited by theory, it is believed that the Sigma-2receptor binders and Sigma-2 receptor activity modulators of the presentinvention can ameliorate, abate, otherwise cause to be controlled,diseases and disorders associated with dysregulation of the sigma-2receptor. The diseases and disorders include, but are not limited toneuropsychiatric disorders such as generalized anxiety disorder, socialanxiety disorder, panic disorder, agoraphobia, obsessive-compulsivedisorder post-traumatic stress disorder, depression, bipolar disorder,anorexia nervosa, bulimia nervosa, substance use disorders, andschizophrenia, cancers such as pancreatic cancer, lung cancer, breastcancer, melanoma, prostate cancer, and ovarian cancer, as well asAlzheimer's disease, mild cognitive impairments, and memory disorders.

The Sigma-2 receptor binders and Sigma-2 receptor activity modulators ofthe present invention are also capable of treating and preventingdiseases associated with overexpression of the sigma-2 receptor, forexample neuropsychiatric disorders such as generalized anxiety disorder,social anxiety disorder, panic disorder, agoraphobia,obsessive-compulsive disorder post-traumatic stress disorder,depression, bipolar disorder, anorexia nervosa, bulimia nervosa,substance use disorders, and schizophrenia, cancers such as pancreaticcancer, lung cancer, breast cancer, melanoma, prostate cancer, andovarian cancer, as well as Alzheimer's disease, mild cognitiveimpairments, and memory disorders. Without wishing to be limited bytheory, it is believed that the Sigma-2 receptor binders and Sigma-2receptor activity modulators of the present invention can ameliorate,abate, otherwise cause to be controlled, diseases and disordersassociated with overexpression of the sigma-2 receptor. The diseases anddisorders include, but are not limited to neuropsychiatric disorderssuch as generalized anxiety disorder, social anxiety disorder, panicdisorder, agoraphobia, obsessive-compulsive disorder post-traumaticstress disorder, depression, bipolar disorder, anorexia nervosa, bulimianervosa, substance use disorders, and schizophrenia, cancers such aspancreatic cancer, lung cancer, breast cancer, melanoma, prostatecancer, and ovarian cancer, as well as Alzheimer's disease, mildcognitive impairments, and memory disorders.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present teachings also consistessentially of, or consist of, the recited components, and that theprocesses of the present teachings also consist essentially of, orconsist of, the recited processing steps.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components and can be selected from a groupconsisting of two or more of the recited elements or components.

The use of the singular herein includes the plural (and vice versa)unless specifically stated otherwise. In addition, where the use of theterm “about” is before a quantitative value, the present teachings alsoinclude the specific quantitative value itself, unless specificallystated otherwise.

It should be understood that the order of steps or order for performingcertain actions is immaterial so long as the present teachings remainoperable. Moreover, two or more steps or actions can be conductedsimultaneously.

As used herein, the term “halogen” shall mean chlorine, bromine,fluorine and iodine.

As used herein, unless otherwise noted, “alkyl” and/or “aliphatic”whether used alone or as part of a substituent group refers to straightand branched carbon chains having 1 to 20 carbon atoms or any numberwithin this range, for example 1 to 6 carbon atoms or 1 to 4 carbonatoms. Designated numbers of carbon atoms (e.g. C₁₋₆) shall referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger alkyl-containing substituent. Non-limitingexamples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. Alkyl groupscan be optionally substituted. Non-limiting examples of substitutedalkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl,aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl,3-carboxypropyl, and the like. In substituent groups with multiple alkylgroups such as (C₁₋₆alkyl)₂amino, the alkyl groups may be the same ordifferent.

As used herein, the terms “alkenyl” and “alkynyl” groups, whether usedalone or as part of a substituent group, refer to straight and branchedcarbon chains having 2 or more carbon atoms, preferably 2 to 20, whereinan alkenyl chain has at least one double bond in the chain and analkynyl chain has at least one triple bond in the chain. Alkenyl andalkynyl groups can be optionally substituted. Nonlimiting examples ofalkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also2-methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, andthe like. Nonlimiting examples of substituted alkenyl groups include2-chloroethenyl (also 2-chlorovinyl), 4-hydroxybuten-1-yl,7-hydroxy-7-methyloct-4-en-2-yl, 7-hydroxy-7-methyloct-3,5-dien-2-yl,and the like. Nonlimiting examples of alkynyl groups include ethynyl,prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl.Nonlimiting examples of substituted alkynyl groups include,5-hydroxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl,5-hydroxy-5-ethylhept-3-ynyl, and the like.

As used herein, “cycloalkyl,” whether used alone or as part of anothergroup, refers to a non-aromatic carbon-containing ring includingcyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms,or even 3 to 4 ring carbon atoms, and optionally containing one or more(e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can bemonocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused,bridged, and/or spiro ring systems), wherein the carbon atoms arelocated inside or outside of the ring system. Any suitable ring positionof the cycloalkyl group can be covalently linked to the defined chemicalstructure. Cycloalkyl rings can be optionally substituted. Nonlimitingexamples of cycloalkyl groups include: cyclopropyl,2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl,2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl,decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl,4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl,octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl,decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, anddodecahydro-1H-fluorenyl. The term “cycloalkyl” also includescarbocyclic rings which are bicyclic hydrocarbon rings, non-limitingexamples of which include, bicyclo-[2.1.1]hexanyl,bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl,1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, andbicyclo[3.3.3]undecanyl.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen. Haloalkyl groupsinclude perhaloalkyl groups, wherein all hydrogens of an alkyl grouphave been replaced with halogens (e.g., —CF₃, —CF₂CF₃). Haloalkyl groupscan optionally be substituted with one or more substituents in additionto halogen. Examples of haloalkyl groups include, but are not limitedto, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl,pentafluoroethyl, and pentachloroethyl groups.

The term “alkoxy” refers to the group —O-alkyl, wherein the alkyl groupis as defined above. Alkoxy groups optionally may be substituted. Theterm C₃-C₆ cyclic alkoxy refers to a ring containing 3 to 6 carbon atomsand at least one oxygen atom (e.g., tetrahydrofuran,tetrahydro-2H-pyran). C₃-C₆ cyclic alkoxy groups optionally may besubstituted.

The term “haloalkoxy” refers to the group —O-haloalkyl, wherein thehaloalkyl group is as defined above. Examples of haloalkoxy groupsinclude, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, and pentafluoroethoxyl.

The term “aryl,” wherein used alone or as part of another group, isdefined herein as a an unsaturated, aromatic monocyclic ring of 6 carbonmembers or to an unsaturated, aromatic polycyclic ring of from 10 to 14carbon members. Aryl rings can be, for example, phenyl or naphthyl ringeach optionally substituted with one or more moieties capable ofreplacing one or more hydrogen atoms. Non-limiting examples of arylgroups include: phenyl, naphthylen-1-yl, naphthylen-2-yl,4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl,2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl,3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1-yl,and 6-cyano-naphthylen-1-yl. Aryl groups also include, for example,phenyl or naphthyl rings fused with one or more saturated or partiallysaturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl,indanyl), which can be substituted at one or more carbon atoms of thearomatic and/or saturated or partially saturated rings.

The term “arylalkyl” or “aralkyl” refers to the group -alkyl-aryl, wherethe alkyl and aryl groups are as defined herein. Aralkyl groups of thepresent invention are optionally substituted. Examples of arylalkylgroups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.

The terms “heterocyclic” and/or “heterocycle” and/or “heterocyclyl,”whether used alone or as part of another group, are defined herein asone or more ring having from 3 to 20 atoms wherein at least one atom inat least one ring is a heteroatom selected from nitrogen (N), oxygen(O), or sulfur (S), and wherein further the ring that includes theheteroatom is non-aromatic. In heterocycle groups that include 2 or morefused rings, the non-heteroatom bearing ring may be aryl (e.g.,indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclegroups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Oneor more N or S atoms in a heterocycle group can be oxidized. Heterocyclegroups can be optionally substituted.

Non-limiting examples of heterocyclic units having a single ringinclude: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl,imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl,isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl,hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl,piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl(valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole,and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclicunits having 2 or more rings include: hexahydro-1H-pyrrolizinyl,3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl,3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl,chromanyl, isochromanyl, indolinyl, isoindolinyl, anddecahydro-1H-cycloocta[b]pyrrolyl.

The term “heteroaryl,” whether used alone or as part of another group,is defined herein as one or more rings having from 5 to 20 atoms whereinat least one atom in at least one ring is a heteroatom chosen fromnitrogen (N), oxygen (O), or sulfur (S), and wherein further at leastone of the rings that includes a heteroatom is aromatic. In heteroarylgroups that include 2 or more fused rings, the non-heteroatom bearingring may be a carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidine) oraryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplaryheteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5ring heteroatoms independently selected from nitrogen (N), oxygen (O),or sulfur (S). One or more N or S atoms in a heteroaryl group can beoxidized. Heteroaryl groups can be substituted. Non-limiting examples ofheteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl,oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl,pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limitingexamples of heteroaryl rings containing 2 or more fused rings include:benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl,9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl,7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl,quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl,8-hydroxy-quinolinyl, 1H-benzo[d]imidazol-2(3H)-onyl,1H-benzo[d]imidazolyl, and isoquinolinyl.

One non-limiting example of a heteroaryl group as described above isC₁-C₅ heteroaryl, which has 1 to 5 carbon ring atoms and at least oneadditional ring atom that is a heteroatom (preferably 1 to 4 additionalring atoms that are heteroatoms) independently selected from nitrogen(N), oxygen (O), or sulfur (S). Examples of C₁-C₅ heteroaryl include,but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl,imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl,furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, andpyridin-4-yl.

Unless otherwise noted, when two substituents are taken together to forma ring having a specified number of ring atoms (e.g., R² and R³ takentogether with the nitrogen (N) to which they are attached to form a ringhaving from 3 to 7 ring members), the ring can have carbon atoms andoptionally one or more (e.g., 1 to 3) additional heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Thering can be saturated or partially saturated and can be optionallysubstituted.

For the purposed of the present invention fused ring units, as well asspirocyclic rings, bicyclic rings and the like, which comprise a singleheteroatom will be considered to belong to the cyclic familycorresponding to the heteroatom containing ring. For example,1,2,3,4-tetrahydroquinoline having the formula:

is, for the purposes of the present invention, considered a heterocyclicunit. 6,7-Dihydro-5H-cyclopentapyrimidine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit. When a fused ring unit contains heteroatoms in both a saturatedand an aryl ring, the aryl ring will predominate and determine the typeof category to which the ring is assigned. For example,1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit.

Whenever a term or either of their prefix roots appear in a name of asubstituent the name is to be interpreted as including those limitationsprovided herein. For example, whenever the term “alkyl” or “aryl” oreither of their prefix roots appear in a name of a substituent (e.g.,arylalkyl, alkylamino) the name is to be interpreted as including thoselimitations given above for “alkyl” and “aryl.”

The term “substituted” is used throughout the specification. The term“substituted” is defined herein as a moiety, whether acyclic or cyclic,which has one or more hydrogen atoms replaced by a substituent orseveral (e.g., 1 to 10) substituents as defined herein below. Thesubstituents are capable of replacing one or two hydrogen atoms of asingle moiety at a time. In addition, these substituents can replace twohydrogen atoms on two adjacent carbons to form said substituent, newmoiety or unit. For example, a substituted unit that requires a singlehydrogen atom replacement includes halogen, hydroxyl, and the like. Atwo hydrogen atom replacement includes carbonyl, oximino, and the like.A two hydrogen atom replacement from adjacent carbon atoms includesepoxy, and the like. The term “substituted” is used throughout thepresent specification to indicate that a moiety can have one or more ofthe hydrogen atoms replaced by a substituent. When a moiety is describedas “substituted” any number of the hydrogen atoms may be replaced. Forexample, difluoromethyl is a substituted C₁ alkyl; trifluoromethyl is asubstituted C₁ alkyl; 4-hydroxyphenyl is a substituted aromatic ring;(N,N-dimethyl-5-amino)octanyl is a substituted C₈ alkyl;3-guanidinopropyl is a substituted C₃ alkyl; and 2-carboxypyridinyl is asubstituted heteroaryl.

The variable groups defined herein, e.g., alkyl, alkenyl, alkynyl,cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groupsdefined herein, whether used alone or as part of another group, can beoptionally substituted. Optionally substituted groups will be soindicated.

The following are non-limiting examples of substituents which cansubstitute for hydrogen atoms on a moiety: halogen (chlorine (Cl),bromine (Br), fluorine (F) and iodine (I)), —CN, —NO₂, oxo (═O), —OR¹³,—SR¹³, —N(R¹³)₂, —NR¹³C(O)R¹³, —SO₂R¹³, —SO₂OR¹³, —SO₂N(R¹³)₂, —C(O)R¹³,—C(O)OR¹³, —C(O)N(R¹³)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₁₄ cycloalkyl, aryl, heterocycle, orheteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups isoptionally substituted with 1-10 (e.g., 1-6 or 1-4) groups selectedindependently from halogen, —CN, —NO₂, oxo, and R¹³; wherein R¹³, ateach occurrence, independently is hydrogen, —OR¹⁴, —SR¹⁴, —C(O)R¹⁴,—C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —SO₂R¹⁴, —S(O)₂OR¹⁴, —N(R¹⁴)₂, —NR¹⁴C(O)R¹⁴,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cycloalkyl(e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, or heteroaryl, or two R¹³units taken together with the atom(s) to which they are bound form anoptionally substituted carbocycle or heterocycle wherein said carbocycleor heterocycle has 3 to 7 ring atoms; wherein R¹⁴, at each occurrence,independently is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, cycloalkyl (e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, orheteroaryl, or two R¹⁴ units taken together with the atom(s) to whichthey are bound form an optionally substituted carbocycle or heterocyclewherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms.

In some embodiments, the substituents are selected from

-   -   i) —OR¹⁵; for example, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃;    -   ii) —C(O)R¹⁵; for example, —COCH₃, —COCH₂CH₃, —COCH₂CH₂CH₃;    -   iii) —C(O)OR¹⁵; for example, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃;    -   iv) —C(O)N(R¹⁵)₂; for example, —CONH₂, —CONHCH₃, —CON(CH₃)₂;    -   v) —N(R¹⁵)₂; for example, —NH₂, —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃);    -   vi) halogen: —F, —Cl, —Br, and —I;    -   vii) —CH_(e)X_(g); wherein X is halogen, m is from 0 to 2,        e+g=3; for example, —CH₂F, —CHF₂, —CF₃, —CCl₃, or —CBr₃;    -   viii) —SO₂R¹⁵; for example, —SO₂H; —SO₂CH₃; —SO₂C₆H₅;    -   ix) C₁-C₆ linear, branched, or cyclic alkyl;    -   x) Cyano    -   xi) Nitro;    -   xii) N(R¹⁵)C(O)R¹⁵;    -   xiii) Oxo (═O);    -   xiv) Heterocycle; and    -   xv) Heteroaryl.        wherein each R¹⁵ is independently hydrogen, optionally        substituted C₁-C₆ linear or branched alkyl (e.g., optionally        substituted C₁-C₄ linear or branched alkyl), or optionally        substituted C₃-C₆ cycloalkyl (e.g optionally substituted C₃-C₄        cycloalkyl); or two R¹⁵ units can be taken together to form a        ring comprising 3-7 ring atoms. In certain aspects, each R¹⁵ is        independently hydrogen, C₁-C₆ linear or branched alkyl        optionally substituted with halogen or C₃-C₆ cycloalkyl or C₃-C₆        cycloalkyl.

At various places in the present specification, substituents ofcompounds are disclosed in groups or in ranges. It is specificallyintended that the description include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually discloseC₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅,C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₆, and C₅-C₆, alkyl.

For the purposes of the present invention the terms “compound,”“analog,” and “composition of matter” stand equally well for the sigma-2receptor activity modulators and sigma-2 receptor binders describedherein, including all enantiomeric forms, diastereomeric forms, salts,and the like, and the terms “compound,” “analog,” and “composition ofmatter” are used interchangeably throughout the present specification.

Compounds described herein can contain an asymmetric atom (also referredas a chiral center), and some of the compounds can contain one or moreasymmetric atoms or centers, which can thus give rise to optical isomers(enantiomers) and diastereomers. The present teachings and compoundsdisclosed herein include such enantiomers and diastereomers, as well asthe racemic and resolved, enantiomerically pure R and S stereoisomers,as well as other mixtures of the R and S stereoisomers andpharmaceutically acceptable salts thereof. Optical isomers can beobtained in pure form by standard procedures known to those skilled inthe art, which include, but are not limited to, diastereomeric saltformation, kinetic resolution, and asymmetric synthesis. The presentteachings also encompass cis and trans isomers of compounds containingalkenyl moieties (e.g., alkenes and imines). It is also understood thatthe present teachings encompass all possible regioisomers, and mixturesthereof, which can be obtained in pure form by standard separationprocedures known to those skilled in the art, and include, but are notlimited to, column chromatography, thin-layer chromatography, andhigh-performance liquid chromatography.

Pharmaceutically acceptable salts of compounds of the present teachings,which can have an acidic moiety, can be formed using organic andinorganic bases. Both mono and polyanionic salts are contemplated,depending on the number of acidic hydrogens available for deprotonation.Suitable salts formed with bases include metal salts, such as alkalimetal or alkaline earth metal salts, for example sodium, potassium, ormagnesium salts; ammonia salts and organic amine salts, such as thoseformed with morpholine, thiomorpholine, piperidine, pyrrolidine, amono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-,diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-,di-, or trihydroxy lower alkylamine (e.g., mono-, di- ortriethanolamine). Specific non-limiting examples of inorganic basesinclude NaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, NaH₂PO₄,Na₂HPO₄, and Na₃PO₄. Internal salts also can be formed. Similarly, whena compound disclosed herein contains a basic moiety, salts can be formedusing organic and inorganic acids. For example, salts can be formed fromthe following acids: acetic, propionic, lactic, benzenesulfonic,benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic,ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic,mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic,pamoic, pantothenic, phosphoric, phthalic, propionic, succinic,sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well asother known pharmaceutically acceptable acids.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence (e.g., in N(R⁹)₂, each R⁹ may bethe same or different than the other). Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

The terms “treat” and “treating” and “treatment” as used herein, referto partially or completely alleviating, inhibiting, ameliorating and/orrelieving a condition from which a patient is suspected to suffer.

As used herein, “therapeutically effective” and “effective dose” referto a substance or an amount that elicits a desirable biological activityor effect.

Except when noted, the terms “subject” or “patient” are usedinterchangeably and refer to mammals such as human patients andnon-human primates, as well as experimental animals such as rabbits,rats, and mice, and other animals. Accordingly, the term “subject” or“patient” as used herein means any mammalian patient or subject to whichthe compounds of the invention can be administered. In an exemplaryembodiment of the present invention, to identify subject patients fortreatment according to the methods of the invention, accepted screeningmethods are employed to determine risk factors associated with atargeted or suspected disease or condition or to determine the status ofan existing disease or condition in a subject. These screening methodsinclude, for example, conventional work-ups to determine risk factorsthat may be associated with the targeted or suspected disease orcondition. These and other routine methods allow the clinician to selectpatients in need of therapy using the methods and compounds of thepresent invention.

The Sigma-2 Receptor Binders and Sigma-2 Receptor Activity Modulators

The sigma-2 receptor binders and sigma-2 receptor activity modulators ofthe present invention include all enantiomeric and diastereomeric formsalts thereof having the formula

The present invention is directed toward novel sigma-2 receptor binders,compounds of formula (I),

including hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein:

A is selected from a group consisting of

n is 1, 2, or 3;

R^(1a) and R^(1b) are each independently selected from the groupconsisting of hydrogen, C₁₋₆ linear alkyl, and C₁₋₆ branched alkyl, orR^(1a) and R^(1b) may be taken together with the atom to which they arebound to form a ring having from 3 to 7 ring atoms;

R² is selected from a group consisting of a benzene ring that isoptionally substituted with 0 to 3 R⁴ groups that are not hydrogen, a4-pyridine ring that is optionally substituted with 0 to 2 R⁵ groupsthat are not hydrogen, a 3-pyridine ring that is optionally substitutedwith 0 to 2 R⁵ groups that are not hydrogen, and a 2-pyridine ring thatis optionally substituted with 0 to 2 R⁵ groups that are not hydrogen;

R³ is selected from a group consisting of a benzene ring that isoptionally substituted with 0 to 3 R⁴ groups that are not hydrogen, a4-pyridine ring that is optionally substituted with 0 to 2 R⁵ groupsthat are not hydrogen, a 3-pyridine ring that is optionally substitutedwith 0 to 2 R⁵ groups that are not hydrogen, and a 2-pyridine ring thatis optionally substituted with 0 to 2 R⁵ groups that are not hydrogen;

R⁴ is at each occurrence independently selected from the groupconsisting of hydrogen, OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branchedalkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b);

the terms R^(4a), R^(4b), R^(4C), R^(4d), and R^(4e) may be used todesignate individual R⁴ groups on a benzene ring;

R⁵ is at each occurrence independently selected from the groupconsisting of hydrogen, OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branchedalkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b);

the terms R^(5a), R^(5b), R^(5c), and R^(5d) may be used to designateindividual R⁵ groups on a pyridine ring;

R⁶ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R⁷ is at each occurrence independently selected from the groupconsisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(8a) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(8b) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(9a) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(9b) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(9a) and R^(9b) may be taken together with the atom to which they arebound to form a ring having from 3 to 7 ring atoms optionally containingan oxygen;

R¹⁰ is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R¹¹ is at each occurrence independently selected from the groupconsisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(12a) is at each occurrence independently selected from the groupconsisting of hydrogen, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl; and

R^(12b) is at each occurrence independently selected from the groupconsisting of hydrogen, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl.

In one embodiment, the present invention includes compounds havingformula (II):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof.

In one embodiment, the present invention includes compounds havingformula (IIa):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) arehydrogen and 0 to 3 of R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) areindependently selected from the group consisting of OH, NO₂, halogen,CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linearalkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl,C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), heterocyclyl, —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆linear alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶,CO₂R⁷, CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (IIb):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (IIc):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (IId):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (III):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof.

In one embodiment, the present invention includes compounds havingformula (IIIa):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) arehydrogen and 0 to 3 of R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) areindependently selected from the group consisting of OH, NO₂, halogen,CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linearalkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl,C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆linear alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶,CO₂R⁷, CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (ITb):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (IIIc):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (IId):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (IV):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof.

In one embodiment, the present invention includes compounds havingformula (IVa):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) arehydrogen and 0 to 3 of R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) areindependently selected from the group consisting of OH, NO₂, halogen,CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linearalkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl,C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆linear alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶,CO₂R⁷, CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (IVb):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (IVc):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (IVd):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR^(9b),NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (V):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof.

In one embodiment, the present invention includes compounds havingformula (Va):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) arehydrogen and 0 to 3 of R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) areindependently selected from the group consisting of OH, NO₂, halogen,CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linearalkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl,C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆linear alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶,CO₂R⁷, CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (Vb):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (Vc):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (Vd):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (VI):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof.

In one embodiment, the present invention includes compounds havingformula (VIa):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) arehydrogen and 0 to 3 of R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) areindependently selected from the group consisting of OH, NO₂, halogen,CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linearalkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl,C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆linear alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶,CO₂R⁷, CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (VIb):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (VIc):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (VId):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (VII):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof.

In one embodiment, the present invention includes compounds havingformula (VIIa):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) arehydrogen and 0 to 3 of R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) areindependently selected from the group consisting of OH, NO₂, halogen,CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linearalkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl,C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆linear alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶,CO₂R⁷, CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (VIIb):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (VIIc):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (VIId):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (VIII):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof.

In one embodiment, the present invention includes compounds havingformula (VIIIa):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(4a), R^(4b), R^(4c), R^(4d), and R^(4′) arehydrogen and 0 to 3 of R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) areindependently selected from the group consisting of OH, NO₂, halogen,CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linearalkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl,C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆linear alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶,CO₂R⁷, CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (VIIIb):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (VIIIc):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (VIIId):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (IX):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof.

In one embodiment, the present invention includes compounds havingformula (IXa):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) arehydrogen and 0 to 3 of R^(4a), R^(4b), R^(4c), R^(4d), and R^(4e) areindependently selected from the group consisting of OH, NO₂, halogen,CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linearalkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl,C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆linear alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶,CO₂R⁷, CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (IXb):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (IXc):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In one embodiment, the present invention includes compounds havingformula (IXd):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(5a), R^(5b), R^(5c), and R^(5d), are hydrogenand 0 to 2 of R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷,CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹,NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments A is

In some embodiments A is

In some embodiments n is 1.

In some embodiments n is 2.

In some embodiments n is 3.

In some embodiments R^(1a) is hydrogen.

In some embodiments R^(1a) is C₁₋₆ linear alkyl.

In some embodiments R^(1a) is C₁₋₆ branched alkyl.

In some embodiments R^(1b) is hydrogen.

In some embodiments R^(1b) is C₁₋₆ linear alkyl.

In some embodiments R^(1b) is C₁₋₆ branched alkyl.

In some embodiments R^(1a) and R^(1b) are be taken together with theatom to which they are bound to form a ring having from 3 ring atoms.

In some embodiments R^(1a) and R^(1b) are be taken together with theatom to which they are bound to form a ring having from 4 ring atoms.

In some embodiments R^(1a) and R^(1b) are be taken together with theatom to which they are bound to form a ring having from 5 ring atoms.

In some embodiments R^(1a) and R^(1b) are be taken together with theatom to which they are bound to form a ring having from 6 ring atoms.

In some embodiments R^(1a) and R^(1b) are be taken together with theatom to which they are bound to form a ring having from 7 ring atoms.

In some embodiments R² is a benzene ring that is optionally substitutedwith 0 to 3 R⁴ groups that are not hydrogen.

In some embodiments R² is a 4-pyridine ring that is optionallysubstituted with 0 to 2 R⁵ groups that are not hydrogen.

In some embodiments R² is a 3-pyridine ring that is optionallysubstituted with 0 to 2 R⁵ groups that are not hydrogen.

In some embodiments R² is a 2-pyridine ring that is optionallysubstituted with 0 to 2 R⁵ groups that are not hydrogen.

In some embodiments R³ is a benzene ring that is optionally substitutedwith 0 to 3 R⁴ groups that are not hydrogen.

In some embodiments R³ is a 4-pyridine ring that is optionallysubstituted with 0 to 2 R⁵ groups that are not hydrogen.

In some embodiments R³ is a 3-pyridine ring that is optionallysubstituted with 0 to 2 R⁵ groups. that are not hydrogen

In some embodiments R³ is a 2-pyridine ring that is optionallysubstituted with 0 to 2 R⁵ groups that are not hydrogen.

In some embodiments R⁴ is hydrogen.

In some embodiments R⁴ is OH.

In some embodiments R⁴ is NO₂.

In some embodiments R⁴ is halogen.

In some embodiments R⁴ is CN.

In some embodiments R⁴ is C₁₋₆ linear alkyl.

In some embodiments R⁴ is C₃₋₇ branched alkyl.

In some embodiments R⁴ is C₃₋₇ cycloalkyl.

In some embodiments R⁴ is C₁₋₆ linear alkoxy.

In some embodiments R⁴ is C₃₋₇ branched alkoxy.

In some embodiments R⁴ is C₃₋₇ cycloalkoxy.

In some embodiments R⁴ is C₁₋₆ linear haloalkyl.

In some embodiments R⁴ is C₃₋₇ branched haloalkyl.

In some embodiments R⁴ is C₁₋₆ linear haloalkoxy.

In some embodiments R⁴ is heterocyclyl.

In some embodiments R⁴ is —S(C₁₋₆ linear alkyl).

In some embodiments R⁴ is —S(C₃₋₇ branched alkyl).

In some embodiments R⁴ is —S(C₃₋₇ cycloalkyl).

In some embodiments R⁴ is —SO₂(C₁₋₆ linear alkyl).

In some embodiments R⁴ is —SO₂(C₃₋₇ branched alkyl).

In some embodiments R⁴ is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R⁴ is COR⁶.

In some embodiments R⁴ is CO₂R⁷.

In some embodiments R⁴ is CONR^(8a)R^(8b).

In some embodiments R⁴ is SO₂NR^(8a)R^(8b).

In some embodiments R⁴ is NR^(9a)R^(9b).

In some embodiments R⁴ is NR^(9a)COR¹⁰.

In some embodiments R⁴ is NR^(9a)SO₂R¹¹.

In some embodiments R⁴ is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R^(4a) is hydrogen.

In some embodiments R^(4a) is OH.

In some embodiments R^(4a) is NO₂.

In some embodiments R^(4a) is halogen.

In some embodiments R^(4a) is CN.

In some embodiments R^(4a) is C₁₋₆ linear alkyl.

In some embodiments R^(4a) is C₃₋₇ branched alkyl.

In some embodiments R^(4a) is C₃₋₇ cycloalkyl.

In some embodiments R^(4a) is C₁₋₆ linear alkoxy.

In some embodiments R^(4a) is C₃₋₇ branched alkoxy.

In some embodiments R^(4a) is C₃₋₇ cycloalkoxy.

In some embodiments R^(4a) is C₁₋₆ linear haloalkyl.

In some embodiments R^(4a) is C₃₋₇ branched haloalkyl.

In some embodiments R^(4a) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(4a) is heterocyclyl.

In some embodiments R^(4a) is —S(C₁₋₆ linear alkyl).

In some embodiments R^(4a) is —S(C₃₋₇ branched alkyl).

In some embodiments R^(4a) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(4a) is —SO₂(C₁₋₆ linear alkyl).

In some embodiments R^(4a) is —SO₂(C₃₋₇ branched alkyl).

In some embodiments R^(4a) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(4a) is COR⁶.

In some embodiments R^(4a) is CO₂R⁷.

In some embodiments R^(4a) is CONR^(8a)R^(8b).

In some embodiments R^(4a) is SO₂NR^(8a)R^(8b).

In some embodiments R^(4a) is NR^(9a)R^(9b).

In some embodiments R^(4a) is NR^(9a)COR¹⁰.

In some embodiments R^(4a) is NR^(9a)SO₂R¹¹.

In some embodiments R^(4a) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R^(4b) is hydrogen.

In some embodiments R^(4b) is OH.

In some embodiments R^(4b) is NO₂.

In some embodiments R^(4b) is halogen.

In some embodiments R^(4b) is CN.

In some embodiments R^(4b) is C₁₋₆ linear alkyl.

In some embodiments R^(4b) is C₃₋₇ branched alkyl.

In some embodiments R^(4b) is C₃₋₇ cycloalkyl.

In some embodiments R^(4b) is C₁₋₆ linear alkoxy.

In some embodiments R^(4b) is C₃₋₇ branched alkoxy.

In some embodiments R^(4b) is C₃₋₇ cycloalkoxy.

In some embodiments R^(4b) is C₁₋₆ linear haloalkyl.

In some embodiments R^(4b) is C₃₋₇ branched haloalkyl.

In some embodiments R^(4b) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(b) is heterocyclyl.

In some embodiments R^(4b) is —S(C₁₋₆ linear alkyl).

In some embodiments R^(4b) is —S(C₃₋₇ branched alkyl).

In some embodiments R^(4b) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(4b) is —SO₂(C₁₋₆ linear alkyl).

In some embodiments R^(4b) is —SO₂(C₃₋₇ branched alkyl).

In some embodiments R^(4b) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(4b) is COR⁶.

In some embodiments R^(4b) is CO₂R⁷.

In some embodiments R^(4b) is CONR^(8a)R^(8b).

In some embodiments R^(4b) is SO₂NR^(8a)R^(8b).

In some embodiments R^(4b) is NR^(9a)R^(9b).

In some embodiments R^(4b) is NR^(9a)COR¹⁰.

In some embodiments R^(4b) is NR^(9a)SO₂R¹¹.

In some embodiments R^(4b) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R^(4C) is hydrogen.

In some embodiments R^(4c) is OH.

In some embodiments R^(4c) is NO₂.

In some embodiments R^(4c) is halogen.

In some embodiments R^(4c) is CN.

In some embodiments R^(4C) is C₁₋₆ linear alkyl.

In some embodiments R^(4c) is C₃₋₇ branched alkyl.

In some embodiments R^(4C) is C₃₋₇ cycloalkyl.

In some embodiments R^(4C) is C₁₋₆ linear alkoxy.

In some embodiments R^(4c) is C₃₋₇ branched alkoxy.

In some embodiments R^(4C) is C₃₋₇ cycloalkoxy.

In some embodiments R^(4c) is C₁₋₆ linear haloalkyl.

In some embodiments R^(4c) is C₃₋₇ branched haloalkyl.

In some embodiments R^(4c) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(4c) is heterocyclyl.

In some embodiments R^(4C) is —S(C₁₋₆ linear alkyl).

In some embodiments R^(4C) is —S(C₃₋₇ branched alkyl).

In some embodiments R^(4C) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(4C) is —SO₂(C₁₋₆ linear alkyl).

In some embodiments R^(4C) is —SO₂(C₃₋₇ branched alkyl).

In some embodiments R^(4C) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(4c) is COR⁶.

In some embodiments R^(4c) is CO₂R⁷.

In some embodiments R^(4c) is CONR^(8a)R^(8b).

In some embodiments R^(4c) is SO₂NR^(8a)R^(8b).

In some embodiments R^(4c) is NR^(9a)R⁹.

In some embodiments R^(4c) is NR^(9a)COR¹⁰.

In some embodiments R^(4c) is NR^(9a)SO₂R¹¹.

In some embodiments R^(4c) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R^(4d) is hydrogen.

In some embodiments R^(4d) is OH.

In some embodiments R^(4d) is NO₂.

In some embodiments R^(4d) is halogen.

In some embodiments R^(4d) is CN.

In some embodiments R^(4d) is C₁₋₆ linear alkyl.

In some embodiments R^(4d) is C₃₋₇ branched alkyl.

In some embodiments R^(4d) is C₃₋₇ cycloalkyl.

In some embodiments R^(4d) is C₁₋₆ linear alkoxy.

In some embodiments R^(4d) is C₃₋₇ branched alkoxy.

In some embodiments R^(4d) is C₃₋₇ cycloalkoxy.

In some embodiments R^(4d) is C₁₋₆ linear haloalkyl.

In some embodiments R^(4d) is C₃₋₇ branched haloalkyl.

In some embodiments R^(4d) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(4d) is heterocyclyl.

In some embodiments R^(4d) is —S(C₁₋₆ linear alkyl).

In some embodiments R^(4d) is —S(C₃₋₇ branched alkyl).

In some embodiments R^(4d) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(4d) is —SO₂(C₁₋₆ linear alkyl).

In some embodiments R^(4d) is —SO₂(C₃₋₇ branched alkyl).

In some embodiments R^(4d) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(4d) is COR⁶.

In some embodiments R^(4d) is CO₂R⁷.

In some embodiments R^(4d) is CONR^(8a)R^(8b).

In some embodiments R^(4d) is SO₂NR^(8a)R^(8b).

In some embodiments R^(4d) is NR^(9a)R^(9b).

In some embodiments R^(4d) is NR^(9a)COR¹⁰.

In some embodiments R^(4d) is NR^(9a)SO₂R¹¹.

In some embodiments R^(4d) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R^(4c) is hydrogen.

In some embodiments R^(4c) is OH.

In some embodiments R^(4c) is NO₂.

In some embodiments R^(4c) is halogen.

In some embodiments R^(4c) is CN.

In some embodiments R^(4c) is C₁₋₆ linear alkyl.

In some embodiments R^(4c) is C₃₋₇ branched alkyl.

In some embodiments R^(4c) is C₃₋₇ cycloalkyl.

In some embodiments R^(4c) is C₁₋₆ linear alkoxy.

In some embodiments R^(4c) is C₃₋₇ branched alkoxy.

In some embodiments R^(4c) is C₃₋₇ cycloalkoxy.

In some embodiments R^(4c) is C₁₋₆ linear haloalkyl.

In some embodiments R^(4c) is C₃₋₇ branched haloalkyl.

In some embodiments R^(4c) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(4c) is heterocyclyl.

In some embodiments R^(4c) is —S(C₁₋₆ linear alkyl).

In some embodiments R^(4c) is —S(C₃₋₇ branched alkyl).

In some embodiments R^(4c) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(4c) is —SO₂(C₁₋₆ linear alkyl).

In some embodiments R^(4c) is —SO₂(C₃₋₇ branched alkyl).

In some embodiments R^(4e) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(4c) is COR⁶.

In some embodiments R^(4c) is CO₂R⁷.

In some embodiments R^(4c) is CONR^(8a)R^(8b).

In some embodiments R^(4c) is SO₂NR^(8a)R^(8b).

In some embodiments R^(4a) is NR^(9a)R^(9b).

In some embodiments R^(4c) is NR^(9a)COR¹⁰.

In some embodiments R^(4c) is NR^(9a)SO₂R¹¹.

In some embodiments R^(4c) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R⁵ is hydrogen.

In some embodiments R⁵ is OH.

In some embodiments R⁵ is NO₂.

In some embodiments R⁵ is halogen.

In some embodiments R⁵ is CN.

In some embodiments R⁵ is C₁₋₆ linear alkyl.

In some embodiments R⁵ is C₃₋₇ branched alkyl.

In some embodiments R⁵ is C₃₋₇ cycloalkyl.

In some embodiments R⁵ is C₁₋₆ linear alkoxy.

In some embodiments R⁵ is C₃₋₇ branched alkoxy.

In some embodiments R⁵ is C₃₋₇ cycloalkoxy.

In some embodiments R⁵ is C₁₋₆ linear haloalkyl.

In some embodiments R⁵ is C₃₋₇ branched haloalkyl.

In some embodiments R⁵ is C₁₋₆ linear haloalkoxy.

In some embodiments R⁵ is —S(C₁₋₆ linear alkyl).

In some embodiments R⁵ is —S(C₃₋₇ branched alkyl).

In some embodiments R⁵ is —S(C₃₋₇ cycloalkyl).

In some embodiments R⁵ is —SO₂(C₁₋₆ linear alkyl).

In some embodiments R⁵ is —SO₂(C₃₋₇ branched alkyl).

In some embodiments R⁵ is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R⁵ is COR⁶.

In some embodiments R⁵ is CO₂R⁷.

In some embodiments R⁵ is CONR^(8a)R^(8b).

In some embodiments R⁵ is SO₂NR^(8a)R^(8b).

In some embodiments R⁵ is NR^(9a)R^(9b).

In some embodiments R⁵ is NR^(9a)COR¹⁰.

In some embodiments R⁵ is NR^(9a)SO₂R¹¹.

In some embodiments R⁵ is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R^(5a) is hydrogen.

In some embodiments R^(5a) is OH.

In some embodiments R^(5a) is NO₂.

In some embodiments R^(5a) is halogen.

In some embodiments R^(5a) is CN.

In some embodiments R^(5a) is C₁₋₆ linear alkyl.

In some embodiments R^(5a) is C₃₋₇ branched alkyl.

In some embodiments R^(5a) is C₃₋₇ cycloalkyl.

In some embodiments R^(5a) is C₁₋₆ linear alkoxy.

In some embodiments R^(5a) is C₃₋₇ branched alkoxy.

In some embodiments R^(5a) is C₃₋₇ cycloalkoxy.

In some embodiments R^(5a) is C₁₋₆ linear haloalkyl.

In some embodiments R^(5a) is C₃₋₇ branched haloalkyl.

In some embodiments R^(5a) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(5a) is —S(C₁₋₆ linear alkyl).

In some embodiments R^(5a) is —S(C₃₋₇ branched alkyl).

In some embodiments R^(5a) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(5a) is —SO₂(C₁₋₆ linear alkyl).

In some embodiments R^(5a) is —SO₂(C₃₋₇ branched alkyl).

In some embodiments R^(5a) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(5a) is COR⁶.

In some embodiments R^(5a) is CO₂R⁷.

In some embodiments R^(5a) is CONR^(8a)R^(8b).

In some embodiments R^(5a) is SO₂NR^(8a)R^(8b).

In some embodiments R^(5a) is NR^(9a)R⁹.

In some embodiments R^(5a) is NR^(9a)COR¹⁰.

In some embodiments R^(5a) is NR^(9a)SO₂R¹¹.

In some embodiments R^(5a) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R^(5b) is hydrogen.

In some embodiments R^(5b) is OH.

In some embodiments R^(5b) is NO₂.

In some embodiments R^(5b) is halogen.

In some embodiments R^(5b) is CN.

In some embodiments R^(5b) is C₁₋₆ linear alkyl.

In some embodiments R^(5b) is C₃₋₇ branched alkyl.

In some embodiments R^(5b) is C₃₋₇ cycloalkyl.

In some embodiments R^(5b) is C₁₋₆ linear alkoxy.

In some embodiments R^(5b) is C₃₋₇ branched alkoxy.

In some embodiments R^(5b) is C₃₋₇ cycloalkoxy.

In some embodiments R^(5b) is C₁₋₆ linear haloalkyl.

In some embodiments R^(5b) is C₃₋₇ branched haloalkyl.

In some embodiments R^(5b) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(5b) is —S(C₁₋₆ linear alkyl).

In some embodiments R^(5b) is —S(C₃₋₇ branched alkyl).

In some embodiments R^(5b) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(5b) is —SO₂(C₁₋₆ linear alkyl).

In some embodiments R^(5b) is —SO₂(C₃₋₇ branched alkyl).

In some embodiments R^(5b) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(5b) is COR⁶.

In some embodiments R^(5b) is CO₂R⁷.

In some embodiments R^(5b) is CONR^(8a)R^(8b).

In some embodiments R^(5b) is SO₂NR^(8a)R^(8b).

In some embodiments R^(5b) is NR^(9a)R^(9b).

In some embodiments R^(5b) is NR^(9a)COR¹⁰.

In some embodiments R^(5b) is NR^(9a)SO₂R¹¹.

In some embodiments R^(5b) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R^(5c) is hydrogen.

In some embodiments R^(5c) is OH.

In some embodiments R^(5c) is NO₂.

In some embodiments R^(5c) is halogen.

In some embodiments R^(5c) is CN.

In some embodiments R^(5c) is C₁₋₆ linear alkyl.

In some embodiments R^(5c) is C₃₋₇ branched alkyl.

In some embodiments R^(5c) is C₃₋₇ cycloalkyl.

In some embodiments R^(5c) is C₁₋₆ linear alkoxy.

In some embodiments R^(5c) is C₃₋₇ branched alkoxy.

In some embodiments R^(5c) is C₃₋₇ cycloalkoxy.

In some embodiments R^(5c) is C₁₋₆ linear haloalkyl.

In some embodiments R^(5c) is C₃₋₇ branched haloalkyl.

In some embodiments R^(5c) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(5c) is —S(C₁₋₆ linear alkyl).

In some embodiments R^(5c) is —S(C₃₋₇ branched alkyl).

In some embodiments R^(5c) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(5c) is —SO₂(C₁₋₆ linear alkyl).

In some embodiments R^(5c) is —SO₂(C₃₋₇ branched alkyl).

In some embodiments R^(5c) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(5c) is COR⁶.

In some embodiments R^(5c) is CO₂R⁷.

In some embodiments R^(5c) is CONR^(8a)R^(8b).

In some embodiments R^(5c) is SO₂NR^(8a)R^(8b).

In some embodiments R^(5c) is NR^(9a)R⁹.

In some embodiments R^(5c) is NR^(9a)COR¹⁰.

In some embodiments R^(5c) is NR^(9a)SO₂R¹¹.

In some embodiments R^(5c) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R^(5d) is hydrogen.

In some embodiments R^(5d) is OH.

In some embodiments R^(5d) is NO₂.

In some embodiments R^(5d) is halogen.

In some embodiments R^(5d) is CN.

In some embodiments R^(5d) is C₁₋₆ linear alkyl.

In some embodiments R^(5d) is C₃₋₇ branched alkyl.

In some embodiments R^(5d) is C₃₋₇ cycloalkyl.

In some embodiments R^(5d) is C₁₋₆ linear alkoxy.

In some embodiments R^(5d) is C₃₋₇ branched alkoxy.

In some embodiments R^(5d) is C₃₋₇ cycloalkoxy.

In some embodiments R^(5d) is C₁₋₆ linear haloalkyl.

In some embodiments R^(5d) is C₃₋₇ branched haloalkyl.

In some embodiments R^(5d) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(5d) is —S(C₁₋₆ linear alkyl).

In some embodiments R^(5d) is —S(C₃₋₇ branched alkyl).

In some embodiments R^(5d) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(5d) is —SO₂(C₁₋₆ linear alkyl).

In some embodiments R^(5d) is —SO₂(C₃₋₇ branched alkyl).

In some embodiments R^(5d) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(5d) is COR⁶.

In some embodiments R^(5d) is CO₂R⁷.

In some embodiments R^(5d) is CONR^(8a)R^(8b).

In some embodiments R^(5d) is SO₂NR^(8a)R^(8b).

In some embodiments R^(5d) is NR^(9a)R^(9b).

In some embodiments R^(5d) is NR^(9a)COR¹⁰.

In some embodiments R^(5d) is NR^(9a)SO₂R¹¹.

In some embodiments R^(5d) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R⁶ is hydrogen.

In some embodiments R⁶ is C₁₋₆ linear alkyl.

In some embodiments R⁶ is C₃₋₇ branched alkyl.

In some embodiments R⁶ is C₃₋₇ cycloalkyl.

In some embodiments R⁷ is C₁₋₆ linear alkyl.

In some embodiments R⁷ is C₃₋₇ branched alkyl.

In some embodiments R⁷ is C₃₋₇ cycloalkyl.

In some embodiments R^(8a) is hydrogen.

In some embodiments R^(8a) is C₁₋₆ linear alkyl.

In some embodiments R^(8a) is C₃₋₇ branched alkyl.

In some embodiments R^(8a) is C₃₋₇ cycloalkyl.

In some embodiments R^(8b) is hydrogen.

In some embodiments R^(8b) is C₁₋₆ linear alkyl.

In some embodiments R^(8b) is C₃₋₇ branched alkyl.

In some embodiments R^(8b) is C₃₋₇ cycloalkyl.

In some embodiments R^(9a) is hydrogen.

In some embodiments R^(9a) is C₁₋₆ linear alkyl.

In some embodiments R^(9a) is C₃₋₇ branched alkyl.

In some embodiments R^(9a) is C₃₋₇ cycloalkyl.

In some embodiments R^(9b) is hydrogen.

In some embodiments R^(9b) is C₁₋₆ linear alkyl.

In some embodiments R^(9b) is C₃₋₇ branched alkyl.

In some embodiments R^(9b) is C₃₋₇ cycloalkyl.

In some embodiments R^(9a) and R^(9b) are be taken together with theatom to which they are bound to form a ring having 3 ring atoms.

In some embodiments R^(9a) and R^(9b) are be taken together with theatom to which they are bound to form a ring having 4 ring atoms.

In some embodiments R^(9a) and R^(9b) are be taken together with theatom to which they are bound to form a ring having 5 ring atoms.

In some embodiments R^(9a) and R^(9b) are be taken together with theatom to which they are bound to form a ring having 6 ring atomsoptionally containing an oxygen.

In some embodiments R^(9a) and R^(9b) are be taken together with theatom to which they are bound to form a ring having 7 ring atomsoptionally containing an oxygen.

In some embodiments R¹⁰ is hydrogen.

In some embodiments R¹⁰ is C₁₋₆ linear alkyl.

In some embodiments R¹⁰ is C₃₋₇ branched alkyl.

In some embodiments R¹⁰ is C₃₋₇ cycloalkyl.

In some embodiments R¹¹ is hydrogen.

In some embodiments R¹¹ is C₁₋₆ linear alkyl.

In some embodiments R¹¹ is C₃₋₇ branched alkyl.

In some embodiments R¹¹ is C₃₋₇ cycloalkyl.

In some embodiments R^(12a) is hydrogen.

In some embodiments R^(12a) is C₁₋₆ linear alkyl.

In some embodiments R^(12a) is C₃₋₇ branched alkyl.

In some embodiments R^(12a) is C₃₋₇ cycloalkyl.

In some embodiments R^(12b) is hydrogen.

In some embodiments R^(12b) is C₁₋₆ linear alkyl.

In some embodiments R^(12b) is C₃₋₇ branched alkyl.

In some embodiments R^(12b) is C₃₋₇ cycloalkyl.

Examples of compounds of the invention include, but are not limited to:

-   (R)-3-(2-(6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:-   (S)-3-(2-(6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one-   (R)-3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (S)-3-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (R)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (S)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (R)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (S)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (R)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (S)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (R)-3-(2-(6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (S)-3-(2-(6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (R)-3-(2-(6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (S)-3-(2-(6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (R)-3-(2-(6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (S)-3-(2-(6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (R)-3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile;-   (S)-2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile;-   (R)-3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile;-   (S)-3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile;-   (R)-4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile;-   (S)-4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile;-   (R)-3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:-   (S)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   or a pharmaceutically acceptable form thereof.

Exemplary embodiments include compounds having the formula (II) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R^(1a), R^(1b), R² and n are definedherein below in Table 1.

TABLE 1 Entry n R^(1a) R^(1b) R² 1 1 CH₃ CH₃ Phenyl 2 2 CH₃ CH₃ Phenyl 33 CH₃ CH₃ Phenyl 4 1 CH₂CH₃ CH₂CH₃ Phenyl 5 2 CH₂CH₃ CH₂CH₃ Phenyl 6 3CH₂CH₃ CH₂CH₃ Phenyl 7 1 CH₃ CH₃ 4-OH-phenyl 8 2 CH₃ CH₃ 4-OH-phenyl 103 CH₃ CH₃ 4-OH-phenyl 11 1 CH₂CH₃ CH₂CH₃ 4-OH-phenyl 12 2 CH₂CH₃ CH₂CH₃4-OH-phenyl 13 3 CH₂CH₃ CH₂CH₃ 4-OH-phenyl 14 1 CH₃ CH₃ 3-OH-phenyl 15 2CH₃ CH₃ 3-OH-phenyl 16 3 CH₃ CH₃ 3-OH-phenyl 17 1 CH₂CH₃ CH₂CH₃3-OH-phenyl 18 2 CH₂CH₃ CH₂CH₃ 3-OH-phenyl 19 3 CH₂CH₃ CH₂CH₃3-OH-phenyl 20 1 CH₃ CH₃ 2-OH-phenyl 21 2 CH₃ CH₃ 2-OH-phenyl 22 3 CH₃CH₃ 2-OH-phenyl 23 1 CH₂CH₃ CH₂CH₃ 2-OH-phenyl 24 2 CH₂CH₃ CH₂CH₃2-OH-phenyl 25 3 CH₂CH₃ CH₂CH₃ 2-OH-phenyl 26 1 CH₃ CH₃ 4-CH₃-Phenyl 272 CH₃ CH₃ 4-CH₃-Phenyl 28 3 CH₃ CH₃ 4-CH₃-Phenyl 26 1 CH₂CH₃ CH₂CH₃4-CH₃-Phenyl 30 2 CH₂CH₃ CH₂CH₃ 4-CH₃-Phenyl 31 3 CH₂CH₃ CH₂CH₃4-CH₃-Phenyl 32 1 CH₃ CH₃ 3-CH₃-Phenyl 33 2 CH₃ CH₃ 3-CH₃-Phenyl 34 3CH₃ CH₃ 3-CH₃-Phenyl 35 1 CH₂CH₃ CH₂CH₃ 3-CH₃-Phenyl 36 2 CH₂CH₃ CH₂CH₃3-CH₃-Phenyl 37 3 CH₂CH₃ CH₂CH₃ 3-CH₃-Phenyl 38 1 CH₃ CH₃ 2-CH₃-Phenyl39 2 CH₃ CH₃ 2-CH₃-Phenyl 40 3 CH₃ CH₃ 2-CH₃-Phenyl 41 1 CH₂CH₃ CH₂CH₃2-CH₃-Phenyl 42 2 CH₂CH₃ CH₂CH₃ 2-CH₃-Phenyl 43 3 CH₂CH₃ CH₂CH₃2-CH₃-Phenyl 44 1 CH₃ CH₃ 4-OCH₃-Phenyl 45 2 CH₃ CH₃ 4-OCH₃-Phenyl 46 3CH₃ CH₃ 4-OCH₃-Phenyl 47 1 CH₂CH₃ CH₂CH₃ 4-OCH₃-Phenyl 48 2 CH₂CH₃CH₂CH₃ 4-OCH₃-Phenyl 49 3 CH₂CH₃ CH₂CH₃ 4-OCH₃-Phenyl 50 1 CH₃ CH₃3-OCH₃-Phenyl 51 2 CH₃ CH₃ 3-OCH₃-Phenyl 52 3 CH₃ CH₃ 3-OCH₃-Phenyl 53 1CH₂CH₃ CH₂CH₃ 3-OCH₃-Phenyl 54 2 CH₂CH₃ CH₂CH₃ 3-OCH₃-Phenyl 55 3 CH₂CH₃CH₂CH₃ 3-OCH₃-Phenyl 56 1 CH₃ CH₃ 2-OCH₃-Phenyl 57 2 CH₃ CH₃2-OCH₃-Phenyl 58 3 CH₃ CH₃ 2-OCH₃-Phenyl 59 1 CH₂CH₃ CH₂CH₃2-OCH₃-Phenyl 60 2 CH₂CH₃ CH₂CH₃ 2-OCH₃-Phenyl 61 3 CH₂CH₃ CH₂CH₃2-OCH₃-Phenyl 62 1 CH₃ CH₃ 4-CN-Phenyl 63 2 CH₃ CH₃ 4-CN-Phenyl 64 3 CH₃CH₃ 4-CN-Phenyl 65 1 CH₂CH₃ CH₂CH₃ 4-CN-Phenyl 66 2 CH₂CH₃ CH₂CH₃4-CN-Phenyl 67 3 CH₂CH₃ CH₂CH₃ 4-CN-Phenyl 68 1 CH₃ CH₃ 3-CN-Phenyl 69 2CH₃ CH₃ 3-CN-Phenyl 70 3 CH₃ CH₃ 3-CN-Phenyl 71 1 CH₂CH₃ CH₂CH₃3-CN-Phenyl 72 2 CH₂CH₃ CH₂CH₃ 3-CN-Phenyl 73 3 CH₂CH₃ CH₂CH₃3-CN-Phenyl 74 1 CH₃ CH₃ 2-CN-Phenyl 75 2 CH₃ CH₃ 2-CN-Phenyl 76 3 CH₃CH₃ 2-CN-Phenyl 77 1 CH₂CH₃ CH₂CH₃ 2-CN-Phenyl 78 2 CH₂CH₃ CH₂CH₃2-CN-Phenyl 79 3 CH₂CH₃ CH₂CH₃ 2-CN-Phenyl 80 1 CH₃ CH₃ 4-F-Phenyl 81 2CH₃ CH₃ 4-F-Phenyl 82 3 CH₃ CH₃ 4-F-Phenyl 83 1 CH₂CH₃ CH₂CH₃ 4-F-Phenyl84 2 CH₂CH₃ CH₂CH₃ 4-F-Phenyl 85 3 CH₂CH₃ CH₂CH₃ 4-F-Phenyl 86 1 CH₃ CH₃3-F-Phenyl 87 2 CH₃ CH₃ 3-F-Phenyl 88 3 CH₃ CH₃ 3-F-Phenyl 89 1 CH₂CH₃CH₂CH₃ 3-F-Phenyl 90 2 CH₂CH₃ CH₂CH₃ 3-F-Phenyl 91 3 CH₂CH₃ CH₂CH₃3-F-Phenyl 92 1 CH₃ CH₃ 2-F-Phenyl 93 2 CH₃ CH₃ 2-F-Phenyl 94 3 CH₃ CH₃2-F-Phenyl 95 1 CH₂CH₃ CH₂CH₃ 2-F-Phenyl 96 2 CH₂CH₃ CH₂CH₃ 2-F-Phenyl97 3 CH₂CH₃ CH₂CH₃ 2-F-Phenyl 98 1 CH₃ CH₃ 4-Cl-Phenyl 99 2 CH₃ CH₃4-Cl-Phenyl 100 3 CH₃ CH₃ 4-Cl-Phenyl 101 1 CH₂CH₃ CH₂CH₃ 4-Cl-Phenyl102 2 CH₂CH₃ CH₂CH₃ 4-Cl-Phenyl 103 3 CH₂CH₃ CH₂CH₃ 4-Cl-Phenyl 104 1CH₃ CH₃ 3-Cl-Phenyl 105 2 CH₃ CH₃ 3-Cl-Phenyl 106 3 CH₃ CH₃ 3-Cl-Phenyl107 1 CH₂CH₃ CH₂CH₃ 3-Cl-Phenyl 108 2 CH₂CH₃ CH₂CH₃ 3-Cl-Phenyl 109 3CH₂CH₃ CH₂CH₃ 3-Cl-Phenyl 110 1 CH₃ CH₃ 2-Cl-Phenyl 111 2 CH₃ CH₃2-Cl-Phenyl 112 3 CH₃ CH₃ 2-Cl-Phenyl 113 1 CH₂CH₃ CH₂CH₃ 2-Cl-Phenyl114 2 CH₂CH₃ CH₂CH₃ 2-Cl-Phenyl 115 3 CH₂CH₃ CH₂CH₃ 2-Cl-Phenyl 116 1CH₃ CH₃ 4-Br-Phenyl 117 2 CH₃ CH₃ 4-Br-Phenyl 118 3 CH₃ CH₃ 4-Br-Phenyl119 1 CH₂CH₃ CH₂CH₃ 4-Br-Phenyl 120 2 CH₂CH₃ CH₂CH₃ 4-Br-Phenyl 121 3CH₂CH₃ CH₂CH₃ 4-Br-Phenyl 122 1 CH₃ CH₃ 4-OCF₃-Phenyl 123 2 CH₃ CH₃4-OCF₃-Phenyl 124 3 CH₃ CH₃ 4-OCF₃-Phenyl 125 1 CH₂CH₃ CH₂CH₃4-OCF₃-Phenyl 126 2 CH₂CH₃ CH₂CH₃ 4-OCF₃-Phenyl 127 3 CH₂CH₃ CH₂CH₃4-OCF₃-Phenyl 128 1 CH₃ CH₃ 3-OCF₃-Phenyl 129 2 CH₃ CH₃ 3-OCF₃-Phenyl130 3 CH₃ CH₃ 3-OCF₃-Phenyl 131 1 CH₂CH₃ CH₂CH₃ 3-OCF₃-Phenyl 132 2CH₂CH₃ CH₂CH₃ 3-OCF₃-Phenyl 133 3 CH₂CH₃ CH₂CH₃ 3-OCF₃-Phenyl 134 1 CH₃CH₃ 2-OCF₃-Phenyl 135 2 CH₃ CH₃ 2-OCF₃-Phenyl 136 3 CH₃ CH₃2-OCF₃-Phenyl 137 1 CH₂CH₃ CH₂CH₃ 2-OCF₃-Phenyl 138 2 CH₂CH₃ CH₂CH₃2-OCF₃-Phenyl 139 3 CH₂CH₃ CH₂CH₃ 2-OCF₃-Phenyl 140 1 CH₃ CH₃4-isopropyl-phenyl 141 2 CH₃ CH₃ 4-isopropyl-phenyl 142 3 CH₃ CH₃4-isopropyl-phenyl 143 1 CH₂CH₃ CH₂CH₃ 4-isopropyl-phenyl 144 2 CH₂CH₃CH₂CH₃ 4-isopropyl-phenyl 145 3 CH₂CH₃ CH₂CH₃ 4-isopropyl-phenyl 146 1CH₃ CH₃ 3-isopropyl-phenyl 147 2 CH₃ CH₃ 3-isopropyl-phenyl 148 3 CH₃CH₃ 3-isopropyl-phenyl 149 1 CH₂CH₃ CH₂CH₃ 3-isopropyl-phenyl 150 2CH₂CH₃ CH₂CH₃ 3-isopropyl-phenyl 151 3 CH₂CH₃ CH₂CH₃ 3-isopropyl-phenyl152 1 CH₃ CH₃ 2-isopropyl-phenyl 153 2 CH₃ CH₃ 2-isopropyl-phenyl 154 3CH₃ CH₃ 2-isopropyl-phenyl 155 1 CH₂CH₃ CH₂CH₃ 2-isopropyl-phenyl 156 2CH₂CH₃ CH₂CH₃ 2-isopropyl-phenyl 157 3 CH₂CH₃ CH₂CH₃ 2-isopropyl-phenyl158 1 CH₃ CH₃ 4-cyclopropyl-phenyl 159 2 CH₃ CH₃ 4-cyclopropyl-phenyl160 3 CH₃ CH₃ 4-cyclopropyl-phenyl 161 1 CH₂CH₃ CH₂CH₃4-cyclopropyl-phenyl 162 2 CH₂CH₃ CH₂CH₃ 4-cyclopropyl-phenyl 163 3CH₂CH₃ CH₂CH₃ 4-cyclopropyl-phenyl 164 1 CH₃ CH₃ 3-cyclopropyl-phenyl165 2 CH₃ CH₃ 3-cyclopropyl-phenyl 166 3 CH₃ CH₃ 3-cyclopropyl-phenyl167 1 CH₂CH₃ CH₂CH₃ 3-cyclopropyl-phenyl 168 2 CH₂CH₃ CH₂CH₃3-cyclopropyl-phenyl 169 3 CH₂CH₃ CH₂CH₃ 3-cyclopropyl-phenyl 170 1 CH₃CH₃ 2-cyclopropyl-phenyl 171 2 CH₃ CH₃ 2-cyclopropyl-phenyl 172 3 CH₃CH₃ 2-cyclopropyl-phenyl 173 1 CH₂CH₃ CH₂CH₃ 2-cyclopropyl-phenyl 174 2CH₂CH₃ CH₂CH₃ 2-cyclopropyl-phenyl 175 3 CH₂CH₃ CH₂CH₃2-cyclopropyl-phenyl 176 1 CH₃ CH₃ 4-morpholino-phenyl 177 2 CH₃ CH₃4-morpholino-phenyl 178 3 CH₃ CH₃ 4-morpholino-phenyl 179 1 CH₂CH₃CH₂CH₃ 4-morpholino-phenyl 180 2 CH₂CH₃ CH₂CH₃ 4-morpholino-phenyl 181 3CH₂CH₃ CH₂CH₃ 4-morpholino-phenyl 182 1 CH₃ CH₃ 3-morpholino-phenyl 1832 CH₃ CH₃ 3-morpholino-phenyl 184 3 CH₃ CH₃ 3-morpholino-phenyl 185 1CH₂CH₃ CH₂CH₃ 3-morpholino-phenyl 186 2 CH₂CH₃ CH₂CH₃3-morpholino-phenyl 187 3 CH₂CH₃ CH₂CH₃ 3-morpholino-phenyl 188 1 CH₃CH₃ 2-morpholino-phenyl 189 2 CH₃ CH₃ 2-morpholino-phenyl 190 3 CH₃ CH₃2-morpholino-phenyl 191 1 CH₂CH₃ CH₂CH₃ 2-morpholino-phenyl 192 2 CH₂CH₃CH₂CH₃ 2-morpholino-phenyl 193 3 CH₂CH₃ CH₂CH₃ 2-morpholino-phenyl 194 1CH₃ CH₃ 2-pyridyl 195 2 CH₃ CH₃ 2-pyridyl 196 3 CH₃ CH₃ 2-pyridyl 197 1CH₂CH₃ CH₂CH₃ 2-pyridyl 198 2 CH₂CH₃ CH₂CH₃ 2-pyridyl 199 3 CH₂CH₃CH₂CH₃ 2-pyridyl 200 1 CH₃ CH₃ 3-pyridyl 201 2 CH₃ CH₃ 3-pyridyl 202 3CH₃ CH₃ 3-pyridyl 203 1 CH₂CH₃ CH₂CH₃ 3-pyridyl 204 2 CH₂CH₃ CH₂CH₃3-pyridyl 205 3 CH₂CH₃ CH₂CH₃ 3-pyridyl 206 1 CH₃ CH₃ 4-pyridyl 207 2CH₃ CH₃ 4-pyridyl 208 3 CH₃ CH₃ 4-pyridyl 209 1 CH₂CH₃ CH₂CH₃ 4-pyridyl210 2 CH₂CH₃ CH₂CH₃ 4-pyridyl 211 3 CH₂CH₃ CH₂CH₃ 4-pyridyl 212 1 CH₃CH₃ 2-CH₃-4-pyridyl 213 2 CH₃ CH₃ 2-CH₃-4-pyridyl 214 3 CH₃ CH₃2-CH₃-4-pyridyl 215 1 CH₂CH₃ CH₂CH₃ 2-CH₃-4-pyridyl 216 2 CH₂CH₃ CH₂CH₃2-CH₃-4-pyridyl 217 3 CH₂CH₃ CH₂CH₃ 2-CH₃-4-pyridyl 218 1 CH₃ CH₃3-CH₃-4-pyridyl 219 2 CH₃ CH₃ 3-CH₃-4-pyridyl 220 3 CH₃ CH₃3-CH₃-4-pyridyl 221 1 CH₂CH₃ CH₂CH₃ 3-CH₃-4-pyridyl 222 2 CH₂CH₃ CH₂CH₃3-CH₃-4-pyridyl 223 3 CH₂CH₃ CH₂CH₃ 3-CH₃-4-pyridyl 224 1 CH₃ CH₃3,5-dimethylpyridin-4-yl 225 2 CH₃ CH₃ 3,5-dimethylpyridin-4-yl 226 3CH₃ CH₃ 3,5-dimethylpyridin-4-yl 227 1 CH₂CH₃ CH₂CH₃3,5-dimethylpyridin-4-yl 228 2 CH₂CH₃ CH₂CH₃ 3,5-dimethylpyridin-4-yl229 3 CH₂CH₃ CH₂CH₃ 3,5-dimethylpyridin-4-yl 230 1 CH₃ CH₃2,6-dimethylpyridin-4-yl 231 2 CH₃ CH₃ 2,6-dimethylpyridin-4-yl 232 3CH₃ CH₃ 2,6-dimethylpyridin-4-yl 233 1 CH₂CH₃ CH₂CH₃2,6-dimethylpyridin-4-yl 234 2 CH₂CH₃ CH₂CH₃ 2,6-dimethylpyridin-4-yl235 3 CH₂CH₃ CH₂CH₃ 2,6-dimethylpyridin-4-yl

Exemplary embodiments include compounds having the formula (X) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 2.

TABLE 2 Entry n R² 1 1 Phenyl 2 2 Phenyl 3 3 Phenyl 4 1 4-OH-phenyl 5 24-OH-phenyl 6 3 4-OH-phenyl 7 1 3-OH-phenyl 8 2 3-OH-phenyl 9 33-OH-phenyl 10 1 2-OH-phenyl 11 2 2-OH-phenyl 12 3 2-OH-phenyl 13 14-CH₃-Phenyl 14 2 4-CH₃-Phenyl 15 3 4-CH₃-Phenyl 16 1 3-CH₃-Phenyl 17 23-CH₃-Phenyl 18 3 3-CH₃-Phenyl 19 1 2-CH₃-Phenyl 20 2 2-CH₃-Phenyl 21 32-CH₃-Phenyl 22 1 4-OCH₃-Phenyl 23 2 4-OCH₃-Phenyl 24 3 4-OCH₃-Phenyl 251 3-OCH₃-Phenyl 26 2 3-OCH₃-Phenyl 27 3 3-OCH₃-Phenyl 28 1 2-OCH₃-Phenyl29 2 2-OCH₃-Phenyl 30 3 2-OCH₃-Phenyl 31 1 4-CN-Phenyl 32 2 4-CN-Phenyl33 3 4-CN-Phenyl 34 1 3-CN-Phenyl 35 2 3-CN-Phenyl 36 3 3-CN-Phenyl 37 12-CN-Phenyl 38 2 2-CN-Phenyl 39 3 2-CN-Phenyl 40 1 4-F-Phenyl 41 24-F-Phenyl 42 3 4-F-Phenyl 43 1 3-F-Phenyl 44 2 3-F-Phenyl 45 33-F-Phenyl 46 1 2-F-Phenyl 47 2 2-F-Phenyl 48 3 2-F-Phenyl 49 14-Cl-Phenyl 50 2 4-Cl-Phenyl 51 3 4-Cl-Phenyl 52 1 3-Cl-Phenyl 53 23-Cl-Phenyl 54 3 3-Cl-Phenyl 55 1 2-Cl-Phenyl 56 2 2-Cl-Phenyl 57 32-Cl-Phenyl 58 1 4-Br-Phenyl 59 2 4-Br-Phenyl 60 3 4-Br-Phenyl 61 14-OCF₃-Phenyl 62 2 4-OCF₃-Phenyl 63 3 4-OCF₃-Phenyl 64 1 4-OCF₃-Phenyl65 2 4-OCF₃-Phenyl 66 3 4-OCF₃-Phenyl 67 1 4-OCF₃-Phenyl 68 24-OCF₃-Phenyl 69 3 4-OCF₃-Phenyl 70 1 4-isopropyl-phenyl 71 24-isopropyl-phenyl 72 3 4-isopropyl-phenyl 73 1 3-isopropyl-phenyl 74 23-isopropyl-phenyl 75 3 3-isopropyl-phenyl 76 1 2-isopropyl-phenyl 77 22-isopropyl-phenyl 78 3 2-isopropyl-phenyl 79 1 4-cyclopropyl-phenyl 802 4-cyclopropyl-phenyl 81 3 4-cyclopropyl-phenyl 82 13-cyclopropyl-phenyl 83 2 3-cyclopropyl-phenyl 84 3 3-cyclopropyl-phenyl85 1 2-cyclopropyl-phenyl 86 2 2-cyclopropyl-phenyl 87 32-cyclopropyl-phenyl 88 1 4-morpholino-phenyl 89 2 4-morpholino-phenyl90 3 4-morpholino-phenyl 91 1 3-morpholino-phenyl 92 23-morpholino-phenyl 93 3 3-morpholino-phenyl 94 1 2-morpholino-phenyl 952 2-morpholino-phenyl 96 3 2-morpholino-phenyl 97 1 2-pyridyl 98 22-pyridyl 99 3 2-pyridyl 100 1 3-pyridyl 101 2 3-pyridyl 102 3 3-pyridyl103 1 4-pyridyl 104 2 4-pyridyl 105 3 4-pyridyl 106 1 2-CH₃-4-pyridyl107 2 2-CH₃-4-pyridyl 108 3 2-CH₃-4-pyridyl 109 1 3-CH₃-4-pyridyl 110 23-CH₃-4-pyridyl 111 3 3-CH₃-4-pyridyl 112 1 3,5-dimethylpyridin-4-yl 1132 3,5-dimethylpyridin-4-yl 114 3 3,5-dimethylpyridin-4-yl 115 12,6-dimethylpyridin-4-yl 116 2 2,6-dimethylpyridin-4-yl 117 32,6-dimethylpyridin-4-yl

Exemplary embodiments include compounds having the formula (XI) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 3.

TABLE 3 Entry n R² 1 1 Phenyl 2 2 Phenyl 3 3 Phenyl 4 1 4-OH-phenyl 5 24-OH-phenyl 6 3 4-OH-phenyl 7 1 3-OH-phenyl 8 2 3-OH-phenyl 9 33-OH-phenyl 10 1 2-OH-phenyl 11 2 2-OH-phenyl 12 3 2-OH-phenyl 13 14-CH₃-Phenyl 14 2 4-CH₃-Phenyl 15 3 4-CH₃-Phenyl 16 1 3-CH₃-Phenyl 17 23-CH₃-Phenyl 18 3 3-CH₃-Phenyl 19 1 2-CH₃-Phenyl 20 2 2-CH₃-Phenyl 21 32-CH₃-Phenyl 22 1 4-OCH₃-Phenyl 23 2 4-OCH₃-Phenyl 24 3 4-OCH₃-Phenyl 251 3-OCH₃-Phenyl 26 2 3-OCH₃-Phenyl 27 3 3-OCH₃-Phenyl 28 1 2-OCH₃-Phenyl29 2 2-OCH₃-Phenyl 30 3 2-OCH₃-Phenyl 31 1 4-CN-Phenyl 32 2 4-CN-Phenyl33 3 4-CN-Phenyl 34 1 3-CN-Phenyl 35 2 3-CN-Phenyl 36 3 3-CN-Phenyl 37 12-CN-Phenyl 38 2 2-CN-Phenyl 39 3 2-CN-Phenyl 40 1 4-F-Phenyl 41 24-F-Phenyl 42 3 4-F-Phenyl 43 1 3-F-Phenyl 44 2 3-F-Phenyl 45 33-F-Phenyl 46 1 2-F-Phenyl 47 2 2-F-Phenyl 48 3 2-F-Phenyl 49 14-Cl-Phenyl 50 2 4-Cl-Phenyl 51 3 4-Cl-Phenyl 52 1 3-Cl-Phenyl 53 23-Cl-Phenyl 54 3 3-Cl-Phenyl 55 1 2-Cl-Phenyl 56 2 2-Cl-Phenyl 57 32-Cl-Phenyl 58 1 4-Br-Phenyl 59 2 4-Br-Phenyl 60 3 4-Br-Phenyl 61 14-OCF₃-Phenyl 62 2 4-OCF₃-Phenyl 63 3 4-OCF₃-Phenyl 64 1 3-OCF₃-Phenyl65 2 3-OCF₃-Phenyl 66 3 3-OCF₃-Phenyl 67 1 2-OCF₃-Phenyl 68 22-OCF₃-Phenyl 69 3 2-OCF₃-Phenyl 70 1 4-isopropyl-phenyl 71 24-isopropyl-phenyl 72 3 4-isopropyl-phenyl 73 1 3-isopropyl-phenyl 74 23-isopropyl-phenyl 75 3 3-isopropyl-phenyl 76 1 2-isopropyl-phenyl 77 22-isopropyl-phenyl 78 3 2-isopropyl-phenyl 79 1 4-cyclopropyl-phenyl 802 4-cyclopropyl-phenyl 81 3 4-cyclopropyl-phenyl 82 13-cyclopropyl-phenyl 83 2 3-cyclopropyl-phenyl 84 3 3-cyclopropyl-phenyl85 1 2-cyclopropyl-phenyl 86 2 2-cyclopropyl-phenyl 87 32-cyclopropyl-phenyl 88 1 4-morpholino-phenyl 89 2 4-morpholino-phenyl90 3 4-morpholino-phenyl 91 1 3-morpholino-phenyl 92 23-morpholino-phenyl 93 3 3-morpholino-phenyl 94 1 2-morpholino-phenyl 952 2-morpholino-phenyl 96 3 2-morpholino-phenyl 97 1 2-pyridyl 98 22-pyridyl 99 3 2-pyridyl 100 1 3-pyridyl 101 2 3-pyridyl 102 3 3-pyridyl103 1 4-pyridyl 104 2 4-pyridyl 105 3 4-pyridyl 106 1 2-CH₃-4-pyridyl107 2 2-CH₃-4-pyridyl 108 3 2-CH₃-4-pyridyl 109 1 3-CH₃-4-pyridyl 110 23-CH₃-4-pyridyl 111 3 3-CH₃-4-pyridyl 112 1 3,5-dimethylpyridin-4-yl 1132 3,5-dimethylpyridin-4-yl 114 3 3,5-dimethylpyridin-4-yl 115 12,6-dimethylpyridin-4-yl 116 2 2,6-dimethylpyridin-4-yl 117 32,6-dimethylpyridin-4-yl

Exemplary embodiments include compounds having the formula (XII) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R and n are defined herein below inTable 4.

TABLE 4 Entry n R² 1 1 Phenyl 2 2 Phenyl 3 3 Phenyl 4 1 4-OH-phenyl 5 24-OH-phenyl 6 3 4-OH-phenyl 7 1 3-OH-phenyl 8 2 3-OH-phenyl 9 33-OH-phenyl 10 1 2-OH-phenyl 11 2 2-OH-phenyl 12 3 2-OH-phenyl 13 14-CH₃-Phenyl 14 2 4-CH₃-Phenyl 15 3 4-CH₃-Phenyl 16 1 3-CH₃-Phenyl 17 23-CH₃-Phenyl 18 3 3-CH₃-Phenyl 19 1 2-CH₃-Phenyl 20 2 2-CH₃-Phenyl 21 32-CH₃-Phenyl 22 1 4-OCH₃-Phenyl 23 2 4-OCH₃-Phenyl 24 3 4-OCH₃-Phenyl 251 3-OCH₃-Phenyl 26 2 3-OCH₃-Phenyl 27 3 3-OCH₃-Phenyl 28 1 2-OCH₃-Phenyl29 2 2-OCH₃-Phenyl 30 3 2-OCH₃-Phenyl 31 1 4-CN-Phenyl 32 2 4-CN-Phenyl33 3 4-CN-Phenyl 34 1 3-CN-Phenyl 35 2 3-CN-Phenyl 36 3 3-CN-Phenyl 37 12-CN-Phenyl 38 2 2-CN-Phenyl 39 3 2-CN-Phenyl 40 1 4-F-Phenyl 41 24-F-Phenyl 42 3 4-F-Phenyl 43 1 3-F-Phenyl 44 2 3-F-Phenyl 45 33-F-Phenyl 46 1 2-F-Phenyl 47 2 2-F-Phenyl 48 3 2-F-Phenyl 49 14-Cl-Phenyl 50 2 4-Cl-Phenyl 51 3 4-Cl-Phenyl 52 1 3-Cl-Phenyl 53 23-Cl-Phenyl 54 3 3-Cl-Phenyl 55 1 2-Cl-Phenyl 56 2 2-Cl-Phenyl 57 32-Cl-Phenyl 58 1 4-Br-Phenyl 59 2 4-Br-Phenyl 60 3 4-Br-Phenyl 61 14-OCF₃-Phenyl 62 2 4-OCF₃-Phenyl 63 3 4-OCF₃-Phenyl 64 1 3-OCF₃-Phenyl65 2 3-OCF₃-Phenyl 66 3 3-OCF₃-Phenyl 67 1 2-OCF₃-Phenyl 68 22-OCF₃-Phenyl 69 3 2-OCF₃-Phenyl 70 1 4-isopropyl-phenyl 71 24-isopropyl-phenyl 72 3 4-isopropyl-phenyl 73 1 3-isopropyl-phenyl 74 23-isopropyl-phenyl 75 3 3-isopropyl-phenyl 76 1 2-isopropyl-phenyl 77 22-isopropyl-phenyl 78 3 2-isopropyl-phenyl 79 1 4-cyclopropyl-phenyl 802 4-cyclopropyl-phenyl 81 3 4-cyclopropyl-phenyl 82 13-cyclopropyl-phenyl 83 2 3-cyclopropyl-phenyl 84 3 3-cyclopropyl-phenyl85 1 2-cyclopropyl-phenyl 86 2 2-cyclopropyl-phenyl 87 32-cyclopropyl-phenyl 88 1 4-morpholino-phenyl 89 2 4-morpholino-phenyl90 3 4-morpholino-phenyl 91 1 3-morpholino-phenyl 92 23-morpholino-phenyl 93 3 3-morpholino-phenyl 94 1 2-morpholino-phenyl 952 2-morpholino-phenyl 96 3 2-morpholino-phenyl 97 1 2-pyridyl 98 22-pyridyl 99 3 2-pyridyl 100 1 3-pyridyl 101 2 3-pyridyl 102 3 3-pyridyl103 1 4-pyridyl 104 2 4-pyridyl 105 3 4-pyridyl 106 1 2-CH₃-4-pyridyl107 2 2-CH₃-4-pyridyl 108 3 2-CH₃-4-pyridyl 109 1 3-CH₃-4-pyridyl 110 23-CH₃-4-pyridyl 111 3 3-CH₃-4-pyridyl 112 1 3,5-dimethylpyridin-4-yl 1132 3,5-dimethylpyridin-4-yl 114 3 3,5-dimethylpyridin-4-yl 115 12,6-dimethylpyridin-4-yl 116 2 2,6-dimethylpyridin-4-yl 117 32,6-dimethylpyridin-4-yl

Exemplary embodiments include compounds having the formula (XIII) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 5.

TABLE 5 Entry n R² 1 1 Phenyl 2 2 Phenyl 3 3 Phenyl 4 1 4-OH-phenyl 5 24-OH-phenyl 6 3 4-OH-phenyl 7 1 3-OH-phenyl 8 2 3-OH-phenyl 9 33-OH-phenyl 10 1 2-OH-phenyl 11 2 2-OH-phenyl 12 3 2-OH-phenyl 13 14-CH₃-Phenyl 14 2 4-CH₃-Phenyl 15 3 4-CH₃-Phenyl 16 1 3-CH₃-Phenyl 17 23-CH₃-Phenyl 18 3 3-CH₃-Phenyl 19 1 2-CH₃-Phenyl 20 2 2-CH₃-Phenyl 21 32-CH₃-Phenyl 22 1 4-OCH₃-Phenyl 23 2 4-OCH₃-Phenyl 24 3 4-OCH₃-Phenyl 251 3-OCH₃-Phenyl 26 2 3-OCH₃-Phenyl 27 3 3-OCH₃-Phenyl 28 1 2-OCH₃-Phenyl29 2 2-OCH₃-Phenyl 30 3 2-OCH₃-Phenyl 31 1 4-CN-Phenyl 32 2 4-CN-Phenyl33 3 4-CN-Phenyl 34 1 3-CN-Phenyl 35 2 3-CN-Phenyl 36 3 3-CN-Phenyl 37 12-CN-Phenyl 38 2 2-CN-Phenyl 39 3 2-CN-Phenyl 40 1 4-F-Phenyl 41 24-F-Phenyl 42 3 4-F-Phenyl 43 1 3-F-Phenyl 44 2 3-F-Phenyl 45 33-F-Phenyl 46 1 2-F-Phenyl 47 2 2-F-Phenyl 48 3 2-F-Phenyl 49 14-Cl-Phenyl 50 2 4-Cl-Phenyl 51 3 4-Cl-Phenyl 52 1 3-Cl-Phenyl 53 23-Cl-Phenyl 54 3 3-Cl-Phenyl 55 1 2-Cl-Phenyl 56 2 2-Cl-Phenyl 57 32-Cl-Phenyl 58 1 4-Br-Phenyl 59 2 4-Br-Phenyl 60 3 4-Br-Phenyl 61 14-OCF₃-Phenyl 62 2 4-OCF₃-Phenyl 63 3 4-OCF₃-Phenyl 64 1 3-OCF₃-Phenyl65 2 3-OCF₃-Phenyl 66 3 3-OCF₃-Phenyl 67 1 2-OCF₃-Phenyl 68 22-OCF₃-Phenyl 69 3 2-OCF₃-Phenyl 70 1 4-isopropyl-phenyl 71 24-isopropyl-phenyl 72 3 4-isopropyl-phenyl 73 1 3-isopropyl-phenyl 74 23-isopropyl-phenyl 75 3 3-isopropyl-phenyl 76 1 2-isopropyl-phenyl 77 22-isopropyl-phenyl 78 3 2-isopropyl-phenyl 79 1 4-cyclopropyl-phenyl 802 4-cyclopropyl-phenyl 81 3 4-cyclopropyl-phenyl 82 13-cyclopropyl-phenyl 83 2 3-cyclopropyl-phenyl 84 3 3-cyclopropyl-phenyl85 1 2-cyclopropyl-phenyl 86 2 2-cyclopropyl-phenyl 87 32-cyclopropyl-phenyl 88 1 4-morpholino-phenyl 89 2 4-morpholino-phenyl90 3 4-morpholino-phenyl 91 1 3-morpholino-phenyl 92 23-morpholino-phenyl 93 3 3-morpholino-phenyl 94 1 2-morpholino-phenyl 952 2-morpholino-phenyl 96 3 2-morpholino-phenyl 97 1 2-pyridyl 98 22-pyridyl 99 3 2-pyridyl 100 1 3-pyridyl 101 2 3-pyridyl 102 3 3-pyridyl103 1 4-pyridyl 104 2 4-pyridyl 105 3 4-pyridyl 106 1 2-CH3-4-pyridyl107 2 2-CH3-4-pyridyl 108 3 2-CH3-4-pyridyl 109 1 3-CH3-4-pyridyl 110 23-CH3-4-pyridyl 111 3 3-CH3-4-pyridyl 112 1 3,5-dimethylpyridin-4-yl 1132 3,5-dimethylpyridin-4-yl 114 3 3,5-dimethylpyridin-4-yl 115 12,6-dimethylpyridin-4-yl 116 2 2,6-dimethylpyridin-4-yl 117 32,6-dimethylpyridin-4-yl

Exemplary embodiments include compounds having the formula (VI) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R^(1a), R^(1b), R³ and n are definedherein below in Table 6.

TABLE 6 Entry n R^(1a) R^(1b) R³ 1 1 CH₃ CH₃ Phenyl 2 2 CH₃ CH₃ Phenyl 33 CH₃ CH₃ Phenyl 4 1 CH₂CH₃ CH₂CH₃ Phenyl 5 2 CH₂CH₃ CH₂CH₃ Phenyl 6 3CH₂CH₃ CH₂CH₃ Phenyl 7 1 CH₃ CH₃ 4-OH-phenyl 8 2 CH₃ CH₃ 4-OH-phenyl 103 CH₃ CH₃ 4-OH-phenyl 11 1 CH₂CH₃ CH₂CH₃ 4-OH-phenyl 12 2 CH₂CH₃ CH₂CH₃4-OH-phenyl 13 3 CH₂CH₃ CH₂CH₃ 4-OH-phenyl 14 1 CH₃ CH₃ 3-OH-phenyl 15 2CH₃ CH₃ 3-OH-phenyl 16 3 CH₃ CH₃ 3-OH-phenyl 17 1 CH₂CH₃ CH₂CH₃3-OH-phenyl 18 2 CH₂CH₃ CH₂CH₃ 3-OH-phenyl 19 3 CH₂CH₃ CH₂CH₃3-OH-phenyl 20 1 CH₃ CH₃ 2-OH-phenyl 21 2 CH₃ CH₃ 2-OH-phenyl 22 3 CH₃CH₃ 2-OH-phenyl 23 1 CH₂CH₃ CH₂CH₃ 2-OH-phenyl 24 2 CH₂CH₃ CH₂CH₃2-OH-phenyl 25 3 CH₂CH₃ CH₂CH₃ 2-OH-phenyl 26 1 CH₃ CH₃ 4-CH₃-Phenyl 272 CH₃ CH₃ 4-CH₃-Phenyl 28 3 CH₃ CH₃ 4-CH₃-Phenyl 26 1 CH₂CH₃ CH₂CH₃4-CH₃-Phenyl 30 2 CH₂CH₃ CH₂CH₃ 4-CH₃-Phenyl 31 3 CH₂CH₃ CH₂CH₃4-CH₃-Phenyl 32 1 CH₃ CH₃ 3-CH₃-Phenyl 33 2 CH₃ CH₃ 3-CH₃-Phenyl 34 3CH₃ CH₃ 3-CH₃-Phenyl 35 1 CH₂CH₃ CH₂CH₃ 3-CH₃-Phenyl 36 2 CH₂CH₃ CH₂CH₃3-CH₃-Phenyl 37 3 CH₂CH₃ CH₂CH₃ 3-CH₃-Phenyl 38 1 CH₃ CH₃ 2-CH₃-Phenyl39 2 CH₃ CH₃ 2-CH₃-Phenyl 40 3 CH₃ CH₃ 2-CH₃-Phenyl 41 1 CH₂CH₃ CH₂CH₃2-CH₃-Phenyl 42 2 CH₂CH₃ CH₂CH₃ 2-CH₃-Phenyl 43 3 CH₂CH₃ CH₂CH₃2-CH₃-Phenyl 44 1 CH₃ CH₃ 4-OCH₃-Phenyl 45 2 CH₃ CH₃ 4-OCH₃-Phenyl 46 3CH₃ CH₃ 4-OCH₃-Phenyl 47 1 CH₂CH₃ CH₂CH₃ 4-OCH₃-Phenyl 48 2 CH₂CH₃CH₂CH₃ 4-OCH₃-Phenyl 49 3 CH₂CH₃ CH₂CH₃ 4-OCH₃-Phenyl 50 1 CH₃ CH₃3-OCH₃-Phenyl 51 2 CH₃ CH₃ 3-OCH₃-Phenyl 52 3 CH₃ CH₃ 3-OCH₃-Phenyl 53 1CH₂CH₃ CH₂CH₃ 3-OCH₃-Phenyl 54 2 CH₂CH₃ CH₂CH₃ 3-OCH₃-Phenyl 55 3 CH₂CH₃CH₂CH₃ 3-OCH₃-Phenyl 56 1 CH₃ CH₃ 2-OCH₃-Phenyl 57 2 CH₃ CH₃2-OCH₃-Phenyl 58 3 CH₃ CH₃ 2-OCH₃-Phenyl 59 1 CH₂CH₃ CH₂CH₃2-OCH₃-Phenyl 60 2 CH₂CH₃ CH₂CH₃ 2-OCH₃-Phenyl 61 3 CH₂CH₃ CH₂CH₃2-OCH₃-Phenyl 62 1 CH₃ CH₃ 4-CN-Phenyl 63 2 CH₃ CH₃ 4-CN-Phenyl 64 3 CH₃CH₃ 4-CN-Phenyl 65 1 CH₂CH₃ CH₂CH₃ 4-CN-Phenyl 66 2 CH₂CH₃ CH₂CH₃4-CN-Phenyl 67 3 CH₂CH₃ CH₂CH₃ 4-CN-Phenyl 68 1 CH₃ CH₃ 3-CN-Phenyl 69 2CH₃ CH₃ 3-CN-Phenyl 70 3 CH₃ CH₃ 3-CN-Phenyl 71 1 CH₂CH₃ CH₂CH₃3-CN-Phenyl 72 2 CH₂CH₃ CH₂CH₃ 3-CN-Phenyl 73 3 CH₂CH₃ CH₂CH₃3-CN-Phenyl 74 1 CH₃ CH₃ 2-CN-Phenyl 75 2 CH₃ CH₃ 2-CN-Phenyl 76 3 CH₃CH₃ 2-CN-Phenyl 77 1 CH₂CH₃ CH₂CH₃ 2-CN-Phenyl 78 2 CH₂CH₃ CH₂CH₃2-CN-Phenyl 79 3 CH₂CH₃ CH₂CH₃ 2-CN-Phenyl 80 1 CH₃ CH₃ 4-F-Phenyl 81 2CH₃ CH₃ 4-F-Phenyl 82 3 CH₃ CH₃ 4-F-Phenyl 83 1 CH₂CH₃ CH₂CH₃ 4-F-Phenyl84 2 CH₂CH₃ CH₂CH₃ 4-F-Phenyl 85 3 CH₂CH₃ CH₂CH₃ 4-F-Phenyl 86 1 CH₃ CH₃3-F-Phenyl 87 2 CH₃ CH₃ 3-F-Phenyl 88 3 CH₃ CH₃ 3-F-Phenyl 89 1 CH₂CH₃CH₂CH₃ 3-F-Phenyl 90 2 CH₂CH₃ CH₂CH₃ 3-F-Phenyl 91 3 CH₂CH₃ CH₂CH₃3-F-Phenyl 92 1 CH₃ CH₃ 2-F-Phenyl 93 2 CH₃ CH₃ 2-F-Phenyl 94 3 CH₃ CH₃2-F-Phenyl 95 1 CH₂CH₃ CH₂CH₃ 2-F-Phenyl 96 2 CH₂CH₃ CH₂CH₃ 2-F-Phenyl97 3 CH₂CH₃ CH₂CH₃ 2-F-Phenyl 98 1 CH₃ CH₃ 4-Cl-Phenyl 99 2 CH₃ CH₃4-Cl-Phenyl 100 3 CH₃ CH₃ 4-Cl-Phenyl 101 1 CH₂CH₃ CH₂CH₃ 4-Cl-Phenyl102 2 CH₂CH₃ CH₂CH₃ 4-Cl-Phenyl 103 3 CH₂CH₃ CH₂CH₃ 4-Cl-Phenyl 104 1CH₃ CH₃ 3-Cl-Phenyl 105 2 CH₃ CH₃ 3-Cl-Phenyl 106 3 CH₃ CH₃ 3-Cl-Phenyl107 1 CH₂CH₃ CH₂CH₃ 3-Cl-Phenyl 108 2 CH₂CH₃ CH₂CH₃ 3-Cl-Phenyl 109 3CH₂CH₃ CH₂CH₃ 3-Cl-Phenyl 110 1 CH₃ CH₃ 2-Cl-Phenyl 111 2 CH₃ CH₃2-Cl-Phenyl 112 3 CH₃ CH₃ 2-Cl-Phenyl 113 1 CH₂CH₃ CH₂CH₃ 2-Cl-Phenyl114 2 CH₂CH₃ CH₂CH₃ 2-Cl-Phenyl 115 3 CH₂CH₃ CH₂CH₃ 2-Cl-Phenyl 116 1CH₃ CH₃ 4-Br-Phenyl 117 2 CH₃ CH₃ 4-Br-Phenyl 118 3 CH₃ CH₃ 4-Br-Phenyl119 1 CH₂CH₃ CH₂CH₃ 4-Br-Phenyl 120 2 CH₂CH₃ CH₂CH₃ 4-Br-Phenyl 121 3CH₂CH₃ CH₂CH₃ 4-Br-Phenyl 122 1 CH₃ CH₃ 4-OCF₃-Phenyl 123 2 CH₃ CH₃4-OCF₃-Phenyl 124 3 CH₃ CH₃ 4-OCF₃-Phenyl 125 1 CH₂CH₃ CH₂CH₃4-OCF₃-Phenyl 126 2 CH₂CH₃ CH₂CH₃ 4-OCF₃-Phenyl 127 3 CH₂CH₃ CH₂CH₃4-OCF₃-Phenyl 128 1 CH₃ CH₃ 3-OCF₃-Phenyl 129 2 CH₃ CH₃ 3-OCF₃-Phenyl130 3 CH₃ CH₃ 3-OCF₃-Phenyl 131 1 CH₂CH₃ CH₂CH₃ 3-OCF₃-Phenyl 132 2CH₂CH₃ CH₂CH₃ 3-OCF₃-Phenyl 133 3 CH₂CH₃ CH₂CH₃ 3-OCF₃-Phenyl 134 1 CH₃CH₃ 2-OCF₃-Phenyl 135 2 CH₃ CH₃ 2-OCF₃-Phenyl 136 3 CH₃ CH₃2-OCF₃-Phenyl 137 1 CH₂CH₃ CH₂CH₃ 2-OCF₃-Phenyl 138 2 CH₂CH₃ CH₂CH₃2-OCF₃-Phenyl 139 3 CH₂CH₃ CH₂CH₃ 2-OCF₃-Phenyl 140 1 CH₃ CH₃4-isopropyl-phenyl 141 2 CH₃ CH₃ 4-isopropyl-phenyl 142 3 CH₃ CH₃4-isopropyl-phenyl 143 1 CH2CH3 CH2CH3 4-isopropyl-phenyl 144 2 CH2CH3CH2CH3 4-isopropyl-phenyl 145 3 CH2CH3 CH2CH3 4-isopropyl-phenyl 146 1CH₃ CH₃ 3-isopropyl-phenyl 147 2 CH₃ CH₃ 3-isopropyl-phenyl 148 3 CH₃CH₃ 3-isopropyl-phenyl 149 1 CH₂CH₃ CH₂CH₃ 3-isopropyl-phenyl 150 2CH₂CH₃ CH₂CH₃ 3-isopropyl-phenyl 151 3 CH₂CH₃ CH₂CH₃ 3-isopropyl-phenyl152 1 CH₃ CH₃ 2-isopropyl-phenyl 153 2 CH₃ CH₃ 2-isopropyl-phenyl 154 3CH₃ CH₃ 2-isopropyl-phenyl 155 1 CH₂CH₃ CH₂CH₃ 2-isopropyl-phenyl 156 2CH₂CH₃ CH₂CH₃ 2-isopropyl-phenyl 157 3 CH₂CH₃ CH₂CH₃ 2-isopropyl-phenyl158 1 CH₃ CH₃ 4-cyclopropyl-phenyl 159 2 CH₃ CH₃ 4-cyclopropyl-phenyl160 3 CH₃ CH₃ 4-cyclopropyl-phenyl 161 1 CH₂CH₃ CH₂CH₃4-cyclopropyl-phenyl 162 2 CH₂CH₃ CH₂CH₃ 4-cyclopropyl-phenyl 163 3CH₂CH₃ CH₂CH₃ 4-cyclopropyl-phenyl 164 1 CH₃ CH₃ 3-cyclopropyl-phenyl165 2 CH₃ CH₃ 3-cyclopropyl-phenyl 166 3 CH₃ CH₃ 3-cyclopropyl-phenyl167 1 CH₂CH₃ CH₂CH₃ 3-cyclopropyl-phenyl 168 2 CH₂CH₃ CH₂CH₃3-cyclopropyl-phenyl 169 3 CH₂CH₃ CH₂CH₃ 3-cyclopropyl-phenyl 170 1 CH₃CH₃ 2-cyclopropyl-phenyl 171 2 CH₃ CH₃ 2-cyclopropyl-phenyl 172 3 CH₃CH₃ 2-cyclopropyl-phenyl 173 1 CH₂CH₃ CH₂CH₃ 2-cyclopropyl-phenyl 174 2CH₂CH₃ CH₂CH₃ 2-cyclopropyl-phenyl 175 3 CH₂CH₃ CH₂CH₃2-cyclopropyl-phenyl 176 1 CH₃ CH₃ 4-morpholino-phenyl 177 2 CH₃ CH₃4-morpholino-phenyl 178 3 CH₃ CH₃ 4-morpholino-phenyl 179 1 CH₂CH₃CH₂CH₃ 4-morpholino-phenyl 180 2 CH₂CH₃ CH₂CH₃ 4-morpholino-phenyl 181 3CH₂CH₃ CH₂CH₃ 4-morpholino-phenyl 182 1 CH₃ CH₃ 3-morpholino-phenyl 1832 CH₃ CH₃ 3-morpholino-phenyl 184 3 CH₃ CH₃ 3-morpholino-phenyl 185 1CH₂CH₃ CH₂CH₃ 3-morpholino-phenyl 186 2 CH₂CH₃ CH₂CH₃3-morpholino-phenyl 187 3 CH₂CH₃ CH₂CH₃ 3-morpholino-phenyl 188 1 CH₃CH₃ 2-morpholino-phenyl 189 2 CH₃ CH₃ 2-morpholino-phenyl 190 3 CH₃ CH₃2-morpholino-phenyl 191 1 CH₂CH₃ CH₂CH₃ 2-morpholino-phenyl 192 2 CH₂CH₃CH₂CH₃ 2-morpholino-phenyl 193 3 CH₂CH₃ CH₂CH₃ 2-morpholino-phenyl 194 1CH₃ CH₃ 2-pyridyl 195 2 CH₃ CH₃ 2-pyridyl 196 3 CH₃ CH₃ 2-pyridyl 197 1CH₂CH₃ CH₂CH₃ 2-pyridyl 198 2 CH₂CH₃ CH₂CH₃ 2-pyridyl 199 3 CH₂CH₃CH₂CH₃ 2-pyridyl 200 1 CH₃ CH₃ 3-pyridyl 201 2 CH₃ CH₃ 3-pyridyl 202 3CH₃ CH₃ 3-pyridyl 203 1 CH₂CH₃ CH₂CH₃ 3-pyridyl 204 2 CH₂CH₃ CH₂CH₃3-pyridyl 205 3 CH₂CH₃ CH₂CH₃ 3-pyridyl 206 1 CH₃ CH₃ 4-pyridyl 207 2CH₃ CH₃ 4-pyridyl 208 3 CH₃ CH₃ 4-pyridyl 209 1 CH₂CH₃ CH₂CH₃ 4-pyridyl210 2 CH₂CH₃ CH₂CH₃ 4-pyridyl 211 3 CH₂CH₃ CH₂CH₃ 4-pyridyl 212 1 CH₃CH₃ 2-CH₃-4-pyridyl 213 2 CH₃ CH₃ 2-CH₃-4-pyridyl 214 3 CH₃ CH₃2-CH₃-4-pyridyl 215 1 CH₂CH₃ CH₂CH₃ 2-CH₃-4-pyridyl 216 2 CH₂CH₃ CH₂CH₃2-CH₃-4-pyridyl 217 3 CH₂CH₃ CH₂CH₃ 2-CH₃-4-pyridyl 218 1 CH₃ CH₃3-CH₃-4-pyridyl 219 2 CH₃ CH₃ 3-CH₃-4-pyridyl 220 3 CH₃ CH₃3-CH₃-4-pyridyl 221 1 CH₂CH₃ CH₂CH₃ 3-CH₃-4-pyridyl 222 2 CH₂CH₃ CH₂CH₃3-CH₃-4-pyridyl 223 3 CH₂CH₃ CH₂CH₃ 3-CH₃-4-pyridyl 224 1 CH₃ CH₃3,5-dimethylpyridin-4-yl 225 2 CH₃ CH₃ 3,5-dimethylpyridin-4-yl 226 3CH₃ CH₃ 3,5-dimethylpyridin-4-yl 227 1 CH₂CH₃ CH₂CH₃3,5-dimethylpyridin-4-yl 228 2 CH₂CH₃ CH₂CH₃ 3,5-dimethylpyridin-4-yl229 3 CH₂CH₃ CH₂CH₃ 3,5-dimethylpyridin-4-yl 230 1 CH₃ CH₃2,6-dimethylpyridin-4-yl 231 2 CH₃ CH₃ 2,6-dimethylpyridin-4-yl 232 3CH₃ CH₃ 2,6-dimethylpyridin-4-yl 233 1 CH₂CH₃ CH₂CH₃2,6-dimethylpyridin-4-yl 234 2 CH₂CH₃ CH₂CH₃ 2,6-dimethylpyridin-4-yl235 3 CH₂CH₃ CH₂CH₃ 2,6-dimethylpyridin-4-yl

Exemplary embodiments include compounds having the formula (XIV) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R³ and n are defined herein below inTable 7.

TABLE 7 Entry n R³ Entry N R³ 1 1 Phenyl 61 1 4-OCF₃-Phenyl 2 2 Phenyl62 2 4-OCF₃-Phenyl 3 3 Phenyl 63 3 4-OCF₃-Phenyl 4 1 4-OH-phenyl 64 13-OCF₃-Phenyl 5 2 4-OH-phenyl 65 2 3-OCF₃-Phenyl 6 3 4-OH-phenyl 66 33-OCF₃-Phenyl 7 1 3-OH-phenyl 67 1 2-OCF₃-Phenyl 8 2 3-OH-phenyl 68 22-OCF₃-Phenyl 9 3 3-OH-phenyl 69 3 2-OCF₃-Phenyl 10 1 2-OH-phenyl 70 14-isopropyl-phenyl 11 2 2-OH-phenyl 71 2 4-isopropyl-phenyl 12 32-OH-phenyl 72 3 4-isopropyl-phenyl 13 1 4-CH₃-Phenyl 73 13-isopropyl-phenyl 14 2 4-CH₃-Phenyl 74 2 3-isopropyl-phenyl 15 34-CH₃-Phenyl 75 3 3-isopropyl-phenyl 16 1 3-CH₃-Phenyl 76 12-isopropyl-phenyl 17 2 3-CH₃-Phenyl 77 2 2-isopropyl-phenyl 18 33-CH₃-Phenyl 78 3 2-isopropyl-phenyl 19 1 2-CH₃-Phenyl 79 14-cyclopropyl-phenyl 20 2 2-CH₃-Phenyl 80 2 4-cyclopropyl-phenyl 21 32-CH₃-Phenyl 81 3 4-cyclopropyl-phenyl 22 1 4-OCH₃-Phenyl 82 13-cyclopropyl-phenyl 23 2 4-OCH₃-Phenyl 83 2 3-cyclopropyl-phenyl 24 34-OCH₃-Phenyl 84 3 3-cyclopropyl-phenyl 25 1 3-OCH₃-Phenyl 85 12-cyclopropyl-phenyl 26 2 3-OCH₃-Phenyl 86 2 2-cyclopropyl-phenyl 27 33-OCH₃-Phenyl 87 3 2-cyclopropyl-phenyl 28 1 2-OCH₃-Phenyl 88 14-morpholino-phenyl 29 2 2-OCH₃-Phenyl 89 2 4-morpholino-phenyl 30 32-OCH₃-Phenyl 90 3 4-morpholino-phenyl 31 1 4-CN-Phenyl 91 13-morpholino-phenyl 32 2 4-CN-Phenyl 92 2 3-morpholino-phenyl 33 34-CN-Phenyl 93 3 3-morpholino-phenyl 34 1 3-CN-Phenyl 94 12-morpholino-phenyl 35 2 3-CN-Phenyl 95 2 2-morpholino-phenyl 36 33-CN-Phenyl 96 3 2-morpholino-phenyl 37 1 2-CN-Phenyl 97 1 2-pyridyl 382 2-CN-Phenyl 98 2 2-pyridyl 39 3 2-CN-Phenyl 99 3 2-pyridyl 40 14-F-Phenyl 100 1 3-pyridyl 41 2 4-F-Phenyl 101 2 3-pyridyl 42 34-F-Phenyl 102 3 3-pyridyl 43 1 3-F-Phenyl 103 1 4-pyridyl 44 23-F-Phenyl 104 2 4-pyridyl 45 3 3-F-Phenyl 105 3 4-pyridyl 46 12-F-Phenyl 106 1 2-CH₃-4-pyridyl 47 2 2-F-Phenyl 107 2 2-CH₃-4-pyridyl48 3 2-F-Phenyl 108 3 2-CH₃-4-pyridyl 49 1 4-Cl-Phenyl 109 13-CH₃-4-pyridyl 50 2 4-Cl-Phenyl 110 2 3-CH₃-4-pyridyl 51 3 4-Cl-Phenyl111 3 3-CH₃-4-pyridyl 52 1 3-Cl-Phenyl 112 1 3,5-dimethylpyridin-4-yl 532 3-Cl-Phenyl 113 2 3,5-dimethylpyridin-4-yl 54 3 3-Cl-Phenyl 114 33,5-dimethylpyridin-4-yl 55 1 2-Cl-Phenyl 115 1 2,6-dimethylpyridin-4-yl56 2 2-Cl-Phenyl 116 2 2,6-dimethylpyridin-4-yl 57 3 2-Cl-Phenyl 117 32,6-dimethylpyridin-4-yl 58 1 4-Br-Phenyl 61 1 59 2 4-Br-Phenyl 62 2 603 4-Br-Phenyl 63 3

Exemplary embodiments include compounds having the formula (XV) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R³ and n are defined herein below inTable 8.

TABLE 8 Entry n R³ Entry N R³ 1 1 Phenyl 61 1 4-OCF₃-Phenyl 2 2 Phenyl62 2 4-OCF₃-Phenyl 3 3 Phenyl 63 3 4-OCF₃-Phenyl 4 1 4-OH-phenyl 64 13-OCF₃-Phenyl 5 2 4-OH-phenyl 65 2 3-OCF₃-Phenyl 6 3 4-OH-phenyl 66 33-OCF₃-Phenyl 7 1 3-OH-phenyl 67 1 2-OCF₃-Phenyl 8 2 3-OH-phenyl 68 22-OCF₃-Phenyl 9 3 3-OH-phenyl 69 3 2-OCF₃-Phenyl 10 1 2-OH-phenyl 70 14-isopropyl-phenyl 11 2 2-OH-phenyl 71 2 4-isopropyl-phenyl 12 32-OH-phenyl 72 3 4-isopropyl-phenyl 13 1 4-CH₃-Phenyl 73 13-isopropyl-phenyl 14 2 4-CH₃-Phenyl 74 2 3-isopropyl-phenyl 15 34-CH₃-Phenyl 75 3 3-isopropyl-phenyl 16 1 3-CH₃-Phenyl 76 12-isopropyl-phenyl 17 2 3-CH₃-Phenyl 77 2 2-isopropyl-phenyl 18 33-CH₃-Phenyl 78 3 2-isopropyl-phenyl 19 1 2-CH₃-Phenyl 79 14-cyclopropyl-phenyl 20 2 2-CH₃-Phenyl 80 2 4-cyclopropyl-phenyl 21 32-CH₃-Phenyl 81 3 4-cyclopropyl-phenyl 22 1 4-OCH₃-Phenyl 82 13-cyclopropyl-phenyl 23 2 4-OCH₃-Phenyl 83 2 3-cyclopropyl-phenyl 24 34-OCH₃-Phenyl 84 3 3-cyclopropyl-phenyl 25 1 3-OCH₃-Phenyl 85 12-cyclopropyl-phenyl 26 2 3-OCH₃-Phenyl 86 2 2-cyclopropyl-phenyl 27 33-OCH₃-Phenyl 87 3 2-cyclopropyl-phenyl 28 1 2-OCH₃-Phenyl 88 14-morpholino-phenyl 29 2 2-OCH₃-Phenyl 89 2 4-morpholino-phenyl 30 32-OCH₃-Phenyl 90 3 4-morpholino-phenyl 31 1 4-CN-Phenyl 91 13-morpholino-phenyl 32 2 4-CN-Phenyl 92 2 3-morpholino-phenyl 33 34-CN-Phenyl 93 3 3-morpholino-phenyl 34 1 3-CN-Phenyl 94 12-morpholino-phenyl 35 2 3-CN-Phenyl 95 2 2-morpholino-phenyl 36 33-CN-Phenyl 96 3 2-morpholino-phenyl 37 1 2-CN-Phenyl 97 1 2-pyridyl 382 2-CN-Phenyl 98 2 2-pyridyl 39 3 2-CN-Phenyl 99 3 2-pyridyl 40 14-F-Phenyl 100 1 3-pyridyl 41 2 4-F-Phenyl 101 2 3-pyridyl 42 34-F-Phenyl 102 3 3-pyridyl 43 1 3-F-Phenyl 103 1 4-pyridyl 44 23-F-Phenyl 104 2 4-pyridyl 45 3 3-F-Phenyl 105 3 4-pyridyl 46 12-F-Phenyl 106 1 2-CH₃-4-pyridyl 47 2 2-F-Phenyl 107 2 2-CH₃-4-pyridyl48 3 2-F-Phenyl 108 3 2-CH₃-4-pyridyl 49 1 4-Cl-Phenyl 109 13-CH₃-4-pyridyl 50 2 4-Cl-Phenyl 110 2 3-CH₃-4-pyridyl 51 3 4-Cl-Phenyl111 3 3-CH₃-4-pyridyl 52 1 3-Cl-Phenyl 112 1 3,5-dimethylpyridin-4-yl 532 3-Cl-Phenyl 113 2 3,5-dimethylpyridin-4-yl 54 3 3-Cl-Phenyl 114 33,5-dimethylpyridin-4-yl 55 1 2-Cl-Phenyl 115 1 2,6-dimethylpyridin-4-yl56 2 2-Cl-Phenyl 116 2 2,6-dimethylpyridin-4-yl 57 3 2-Cl-Phenyl 117 32,6-dimethylpyridin-4-yl 58 1 4-Br-Phenyl 59 2 4-Br-Phenyl 60 34-Br-Phenyl

Exemplary embodiments include compounds having the formula (XVI) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R³ and n are defined herein below inTable 9.

TABLE 9 Entry n R³ Entry n R³ 1 1 Phenyl 61 1 4-OCF₃-Phenyl 2 2 Phenyl62 2 4-OCF₃-Phenyl 3 3 Phenyl 63 3 4-OCF₃-Phenyl 4 1 4-OH-phenyl 64 13-OCF₃-Phenyl 5 2 4-OH-phenyl 65 2 3-OCF₃-Phenyl 6 3 4-OH-phenyl 66 33-OCF₃-Phenyl 7 1 3-OH-phenyl 67 1 2-OCF₃-Phenyl 8 2 3-OH-phenyl 68 22-OCF₃-Phenyl 9 3 3-OH-phenyl 69 3 2-OCF₃-Phenyl 10 1 2-OH-phenyl 70 14-isopropyl-phenyl 11 2 2-OH-phenyl 71 2 4-isopropyl-phenyl 12 32-OH-phenyl 72 3 4-isopropyl-phenyl 13 1 4-CH₃-Phenyl 73 13-isopropyl-phenyl 14 2 4-CH₃-Phenyl 74 2 3-isopropyl-phenyl 15 34-CH₃-Phenyl 75 3 3-isopropyl-phenyl 16 1 3-CH₃-Phenyl 76 12-isopropyl-phenyl 17 2 3-CH₃-Phenyl 77 2 2-isopropyl-phenyl 18 33-CH₃-Phenyl 78 3 2-isopropyl-phenyl 19 1 2-CH₃-Phenyl 79 14-cyclopropyl-phenyl 20 2 2-CH₃-Phenyl 80 2 4-cyclopropyl-phenyl 21 32-CH₃-Phenyl 81 3 4-cyclopropyl-phenyl 22 1 4-OCH₃-Phenyl 82 13-cyclopropyl-phenyl 23 2 4-OCH₃-Phenyl 83 2 3-cyclopropyl-phenyl 24 34-OCH₃-Phenyl 84 3 3-cyclopropyl-phenyl 25 1 3-OCH₃-Phenyl 85 12-cyclopropyl-phenyl 26 2 3-OCH₃-Phenyl 86 2 2-cyclopropyl-phenyl 27 33-OCH₃-Phenyl 87 3 2-cyclopropyl-phenyl 28 1 2-OCH₃-Phenyl 88 14-morpholino-phenyl 29 2 2-OCH₃-Phenyl 89 2 4-morpholino-phenyl 30 32-OCH₃-Phenyl 90 3 4-morpholino-phenyl 31 1 4-CN-Phenyl 91 13-morpholino-phenyl 32 2 4-CN-Phenyl 92 2 3-morpholino-phenyl 33 34-CN-Phenyl 93 3 3-morpholino-phenyl 34 1 3-CN-Phenyl 94 12-morpholino-phenyl 35 2 3-CN-Phenyl 95 2 2-morpholino-phenyl 36 33-CN-Phenyl 96 3 2-morpholino-phenyl 37 1 2-CN-Phenyl 97 1 2-pyridyl 382 2-CN-Phenyl 98 2 2-pyridyl 39 3 2-CN-Phenyl 99 3 2-pyridyl 40 14-F-Phenyl 100 1 3-pyridyl 41 2 4-F-Phenyl 101 2 3-pyridyl 42 34-F-Phenyl 102 3 3-pyridyl 43 1 3-F-Phenyl 103 1 4-pyridyl 44 23-F-Phenyl 104 2 4-pyridyl 45 3 3-F-Phenyl 105 3 4-pyridyl 46 12-F-Phenyl 106 1 2-CH₃-4-pyridyl 47 2 2-F-Phenyl 107 2 2-CH₃-4-pyridyl48 3 2-F-Phenyl 108 3 2-CH₃-4-pyridyl 49 1 4-Cl-Phenyl 109 13-CH₃-4-pyridyl 50 2 4-Cl-Phenyl 110 2 3-CH₃-4-pyridyl 51 3 4-Cl-Phenyl111 3 3-CH₃-4-pyridyl 52 1 3-Cl-Phenyl 112 1 3,5-dimethylpyridin-4-yl 532 3-Cl-Phenyl 113 2 3,5-dimethylpyridin-4-yl 54 3 3-Cl-Phenyl 114 33,5-dimethylpyridin-4-yl 55 1 2-Cl-Phenyl 115 1 2,6-dimethylpyridin-4-yl56 2 2-Cl-Phenyl 116 2 2,6-dimethylpyridin-4-yl 57 3 2-Cl-Phenyl 117 32,6-dimethylpyridin-4-yl 58 1 4-Br-Phenyl 59 2 4-Br-Phenyl 60 34-Br-Phenyl

Exemplary embodiments include compounds having the formula (XVII) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R³ and n are defined herein below inTable 10.

TABLE 10 Entry n R³ Entry n R³ 1 1 Phenyl 61 1 4-OCF₃-Phenyl 2 2 Phenyl62 2 4-OCF₃-Phenyl 3 3 Phenyl 63 3 4-OCF₃-Phenyl 4 1 4-OH-phenyl 64 13-OCF₃-Phenyl 5 2 4-OH-phenyl 65 2 3-OCF₃-Phenyl 6 3 4-OH-phenyl 66 33-OCF₃-Phenyl 7 1 3-OH-phenyl 67 1 2-OCF₃-Phenyl 8 2 3-OH-phenyl 68 22-OCF₃-Phenyl 9 3 3-OH-phenyl 69 3 2-OCF₃-Phenyl 10 1 2-OH-phenyl 70 14-isopropyl-phenyl 11 2 2-OH-phenyl 71 2 4-isopropyl-phenyl 12 32-OH-phenyl 72 3 4-isopropyl-phenyl 13 1 4-CH₃-Phenyl 73 13-isopropyl-phenyl 14 2 4-CH₃-Phenyl 74 2 3-isopropyl-phenyl 15 34-CH₃-Phenyl 75 3 3-isopropyl-phenyl 16 1 3-CH₃-Phenyl 76 12-isopropyl-phenyl 17 2 3-CH₃-Phenyl 77 2 2-isopropyl-phenyl 18 33-CH₃-Phenyl 78 3 2-isopropyl-phenyl 19 1 2-CH₃-Phenyl 79 14-cyclopropyl-phenyl 20 2 2-CH₃-Phenyl 80 2 4-cyclopropyl-phenyl 21 32-CH₃-Phenyl 81 3 4-cyclopropyl-phenyl 22 1 4-OCH₃-Phenyl 82 13-cyclopropyl-phenyl 23 2 4-OCH₃-Phenyl 83 2 3-cyclopropyl-phenyl 24 34-OCH₃-Phenyl 84 3 3-cyclopropyl-phenyl 25 1 3-OCH₃-Phenyl 85 12-cyclopropyl-phenyl 26 2 3-OCH₃-Phenyl 86 2 2-cyclopropyl-phenyl 27 33-OCH₃-Phenyl 87 3 2-cyclopropyl-phenyl 28 1 2-OCH₃-Phenyl 88 14-morpholino-phenyl 29 2 2-OCH₃-Phenyl 89 2 4-morpholino-phenyl 30 32-OCH₃-Phenyl 90 3 4-morpholino-phenyl 31 1 4-CN-Phenyl 91 13-morpholino-phenyl 32 2 4-CN-Phenyl 92 2 3-morpholino-phenyl 33 34-CN-Phenyl 93 3 3-morpholino-phenyl 34 1 3-CN-Phenyl 94 12-morpholino-phenyl 35 2 3-CN-Phenyl 95 2 2-morpholino-phenyl 36 33-CN-Phenyl 96 3 2-morpholino-phenyl 37 1 2-CN-Phenyl 97 1 2-pyridyl 382 2-CN-Phenyl 98 2 2-pyridyl 39 3 2-CN-Phenyl 99 3 2-pyridyl 40 14-F-Phenyl 100 1 3-pyridyl 41 2 4-F-Phenyl 101 2 3-pyridyl 42 34-F-Phenyl 102 3 3-pyridyl 43 1 3-F-Phenyl 103 1 4-pyridyl 44 23-F-Phenyl 104 2 4-pyridyl 45 3 3-F-Phenyl 105 3 4-pyridyl 46 12-F-Phenyl 106 1 2-CH₃-4-pyridyl 47 2 2-F-Phenyl 107 2 2-CH₃-4-pyridyl48 3 2-F-Phenyl 108 3 2-CH₃-4-pyridyl 49 1 4-Cl-Phenyl 109 13-CH₃-4-pyridyl 50 2 4-Cl-Phenyl 110 2 3-CH₃-4-pyridyl 51 3 4-Cl-Phenyl111 3 3-CH₃-4-pyridyl 52 1 3-Cl-Phenyl 112 1 3,5-dimethylpyridin-4-yl 532 3-Cl-Phenyl 113 2 3,5-dimethylpyridin-4-yl 54 3 3-Cl-Phenyl 114 33,5-dimethylpyridin-4-yl 55 1 2-Cl-Phenyl 115 1 2,6-dimethylpyridin-4-yl56 2 2-Cl-Phenyl 116 2 2,6-dimethylpyridin-4-yl 57 3 2-Cl-Phenyl 117 32,6-dimethylpyridin-4-yl 58 1 4-Br-Phenyl 59 2 4-Br-Phenyl 60 34-Br-Phenyl

Exemplary embodiments include compounds having the formula (II) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R^(1a), R^(1b), R² and n are definedherein below in Table 11.

TABLE 11 Entry n R^(1a) R^(1b) R² 1 1 CH₃ CH₃ 2-CF₃-Phenyl 2 2 CH₃ CH₃2-CF₃-Phenyl 3 3 CH₃ CH₃ 2-CF₃-Phenyl 4 1 CH₂CH₃ CH₂CH₃ 2-CF₃-Phenyl 5 2CH₂CH₃ CH₂CH₃ 2-CF₃-Phenyl 6 3 CH₂CH₃ CH₂CH₃ 2-CF₃-Phenyl 7 1 CH₃ CH₃3-CF₃-Phenyl 8 2 CH₃ CH₃ 3-CF₃-Phenyl 9 3 CH₃ CH₃ 3-CF₃-Phenyl 10 1CH₂CH₃ CH₂CH₃ 3-CF₃-Phenyl 11 2 CH₂CH₃ CH₂CH₃ 3-CF₃-Phenyl 12 3 CH₂CH₃CH₂CH₃ 3-CF₃-Phenyl 13 1 CH₃ CH₃ 4-CF₃-Phenyl 14 2 CH₃ CH₃ 4-CF₃-Phenyl15 3 CH₃ CH₃ 4-CF₃-Phenyl 16 1 CH₂CH₃ CH₂CH₃ 4-CF₃-Phenyl 17 2 CH₂CH₃CH₂CH₃ 4-CF₃-Phenyl 18 3 CH₂CH₃ CH₂CH₃ 4-CF₃-Phenyl 19 1 CH₃ CH₃2-NH₂-Phenyl 20 2 CH₃ CH₃ 2-NH₂-Phenyl 21 3 CH₃ CH₃ 2-NH₂-Phenyl 22 1CH₂CH₃ CH₂CH₃ 2-NH₂-Phenyl 23 2 CH₂CH₃ CH₂CH₃ 2-NH₂-Phenyl 24 3 CH₂CH₃CH₂CH₃ 2-NH₂-Phenyl 25 1 CH₃ CH₃ 3-NH₂-Phenyl 26 2 CH₃ CH₃ 3-NH₂-Phenyl27 3 CH₃ CH₃ 3-NH₂-Phenyl 28 1 CH₂CH₃ CH₂CH₃ 3-NH₂-Phenyl 29 2 CH₂CH₃CH₂CH₃ 3-NH₂-Phenyl 30 3 CH₂CH₃ CH₂CH₃ 3-NH₂-Phenyl 31 1 CH₃ CH₃4-NH₂-Phenyl 32 2 CH₃ CH₃ 4-NH₂-Phenyl 33 3 CH₃ CH₃ 4-NH₂-Phenyl 34 1CH₂CH₃ CH₂CH₃ 4-NH₂-Phenyl 35 2 CH₂CH₃ CH₂CH₃ 4-NH₂-Phenyl 36 3 CH₂CH₃CH₂CH₃ 4-NH₂-Phenyl 37 1 CH₃ CH₃ 2-tBu-Phenyl 38 2 CH₃ CH₃ 2-tBu-Phenyl39 3 CH₃ CH₃ 2-tBu-Phenyl 40 1 CH₂CH₃ CH₂CH₃ 2-tBu-Phenyl 41 2 CH₂CH₃CH₂CH₃ 2-tBu-Phenyl 42 3 CH₂CH₃ CH₂CH₃ 2-tBu-Phenyl 43 1 CH₃ CH₃3-tBu-Phenyl 44 2 CH₃ CH₃ 3-tBu-Phenyl 45 3 CH₃ CH₃ 3-tBu-Phenyl 46 1CH₂CH₃ CH₂CH₃ 3-tBu-Phenyl 47 2 CH₂CH₃ CH₂CH₃ 3-tBu-Phenyl 48 3 CH₂CH₃CH₂CH₃ 3-tBu-Phenyl 49 1 CH₃ CH₃ 4-tBu-Phenyl 50 2 CH₃ CH₃ 4-tBu-Phenyl51 3 CH₃ CH₃ 4-tBu-Phenyl 52 1 CH₂CH₃ CH₂CH₃ 4-tBu-Phenyl 53 2 CH₂CH₃CH₂CH₃ 4-tBu-Phenyl 54 3 CH₂CH₃ CH₂CH₃ 4-tBu-Phenyl 55 1 CH₃ CH₃2-NO₂-Phenyl 56 2 CH₃ CH₃ 2-NO₂-Phenyl 57 3 CH₃ CH₃ 2-NO₂-Phenyl 58 1CH₂CH₃ CH₂CH₃ 2-NO₂-Phenyl 59 2 CH₂CH₃ CH₂CH₃ 2-NO₂-Phenyl 60 3 CH₂CH₃CH₂CH₃ 2-NO₂-Phenyl 61 1 CH₃ CH₃ 2-NO₂-Phenyl 62 2 CH₃ CH₃ 2-NO₂-Phenyl63 3 CH₃ CH₃ 2-NO₂-Phenyl 64 1 CH₂CH₃ CH₂CH₃ 2-NO₂-Phenyl 65 2 CH₂CH₃CH₂CH₃ 2-NO₂-Phenyl 66 3 CH₂CH₃ CH₂CH₃ 2-NO₂-Phenyl 67 1 CH₃ CH₃2-NO₂-Phenyl 68 2 CH₃ CH₃ 2-NO₂-Phenyl 69 3 CH₃ CH₃ 2-NO₂-Phenyl 70 1CH₂CH₃ CH₂CH₃ 2-NO₂-Phenyl 71 2 CH₂CH₃ CH₂CH₃ 2-NO₂-Phenyl 72 3 CH₂CH₃CH₂CH₃ 2-NO₂-Phenyl 73 1 CH₃ CH₃ 2-SCH₃-Phenyl 74 2 CH₃ CH₃2-SCH₃-Phenyl 75 3 CH₃ CH₃ 2-SCH₃-Phenyl 76 1 CH₂CH₃ CH₂CH₃2-SCH₃-Phenyl 77 2 CH₂CH₃ CH₂CH₃ 2-SCH₃-Phenyl 78 3 CH₂CH₃ CH₂CH₃2-SCH₃-Phenyl 79 1 CH₃ CH₃ 3-SCH₃-Phenyl 80 2 CH₃ CH₃ 3-SCH₃-Phenyl 81 3CH₃ CH₃ 3-SCH₃-Phenyl 82 1 CH₂CH₃ CH₂CH₃ 3-SCH₃-Phenyl 83 2 CH₂CH₃CH₂CH₃ 3-SCH₃-Phenyl 84 3 CH₂CH₃ CH₂CH₃ 3-SCH₃-Phenyl 85 1 CH₃ CH₃4-SCH₃-Phenyl 86 2 CH₃ CH₃ 4-SCH₃-Phenyl 87 3 CH₃ CH₃ 4-SCH₃-Phenyl 88 1CH₂CH₃ CH₂CH₃ 4-SCH₃-Phenyl 89 2 CH₂CH₃ CH₂CH₃ 4-SCH₃-Phenyl 90 3 CH₂CH₃CH₂CH₃ 4-SCH₃-Phenyl 91 1 CH₃ CH₃ 2-SO₂CH₃-Phenyl 92 2 CH₃ CH₃2-SO₂CH₃-Phenyl 93 3 CH₃ CH₃ 2-SO₂CH₃-Phenyl 94 1 CH₂CH₃ CH₂CH₃2-SO₂CH₃-Phenyl 95 2 CH₂CH₃ CH₂CH₃ 2-SO₂CH₃-Phenyl 96 3 CH₂CH₃ CH₂CH₃2-SO₂CH₃-Phenyl 97 1 CH₃ CH₃ 3-SO₂CH₃-Phenyl 98 2 CH₃ CH₃3-SO₂CH₃-Phenyl 99 3 CH₃ CH₃ 3-SO₂CH₃-Phenyl 100 1 CH₂CH₃ CH₂CH₃3-SO₂CH₃-Phenyl 101 2 CH₂CH₃ CH₂CH₃ 3-SO₂CH₃-Phenyl 102 3 CH₂CH₃ CH₂CH₃3-SO₂CH₃-Phenyl 103 1 CH₃ CH₃ 4-SO₂CH₃-Phenyl 104 2 CH₃ CH₃4-SO₂CH₃-Phenyl 105 3 CH₃ CH₃ 4-SO₂CH₃-Phenyl 106 1 CH₂CH₃ CH₂CH₃4-SO₂CH₃-Phenyl 107 2 CH₂CH₃ CH₂CH₃ 4-SO₂CH₃-Phenyl 108 3 CH₂CH₃ CH₂CH₃4-SO₂CH₃-Phenyl 109 1 CH₃ CH₃ 2-SO₂NH₂-Phenyl 110 2 CH₃ CH₃2-SO₂NH₂-Phenyl 111 3 CH₃ CH₃ 2-SO₂NH₂-Phenyl 112 1 CH₂CH₃ CH₂CH₃2-SO₂NH₂-Phenyl 113 2 CH₂CH₃ CH₂CH₃ 2-SO₂NH₂-Phenyl 114 3 CH₂CH₃ CH₂CH₃2-SO₂NH₂-Phenyl 115 1 CH₃ CH₃ 3-SO₂NH₂-Phenyl 116 2 CH₃ CH₃3-SO₂NH₂-Phenyl 117 3 CH₃ CH₃ 3-SO₂NH₂-Phenyl 118 1 CH₂CH₃ CH₂CH₃3-SO₂NH₂-Phenyl 119 2 CH₂CH₃ CH₂CH₃ 3-SO₂NH₂-Phenyl 120 3 CH₂CH₃ CH₂CH₃3-SO₂NH₂-Phenyl 121 1 CH₃ CH₃ 4-SO₂NH₂-Phenyl 122 2 CH₃ CH₃4-SO₂NH₂-Phenyl 123 3 CH₃ CH₃ 4-SO₂NH₂-Phenyl 124 1 CH₂CH₃ CH₂CH₃4-SO₂NH₂-Phenyl 125 2 CH₂CH₃ CH₂CH₃ 4-SO₂NH₂-Phenyl 126 3 CH₂CH₃ CH₂CH₃4-SO₂NH₂-Phenyl 127 1 CH₃ CH₃ 2-CONH₂-Phenyl 128 2 CH₃ CH₃2-CONH₂-Phenyl 129 3 CH₃ CH₃ 2-CONH₂-Phenyl 130 1 CH₂CH₃ CH₂CH₃2-CONH₂-Phenyl 131 2 CH₂CH₃ CH₂CH₃ 2-CONH₂-Phenyl 132 3 CH₂CH₃ CH₂CH₃2-CONH₂-Phenyl 133 1 CH₃ CH₃ 3-CONH₂-Phenyl 134 2 CH₃ CH₃ 3-CONH₂-Phenyl135 3 CH₃ CH₃ 3-CONH₂-Phenyl 136 1 CH₂CH₃ CH₂CH₃ 3-CONH₂-Phenyl 137 2CH₂CH₃ CH₂CH₃ 3-CONH₂-Phenyl 138 3 CH₂CH₃ CH₂CH₃ 3-CONH₂-Phenyl 139 1CH₃ CH₃ 4-CONH₂-Phenyl 140 2 CH₃ CH₃ 4-CONH₂-Phenyl 141 3 CH₃ CH₃4-CONH₂-Phenyl 142 1 CH₂CH₃ CH₂CH₃ 4-CONH₂-Phenyl 143 2 CH₂CH₃ CH₂CH₃4-CONH₂-Phenyl 144 3 CH₂CH₃ CH₂CH₃ 4-CONH₂-Phenyl 145 1 CH₃ CH₃2-Br-Phenyl 146 2 CH₃ CH₃ 2-Br-Phenyl 147 3 CH₃ CH₃ 2-Br-Phenyl 148 1CH₂CH₃ CH₂CH₃ 2-Br-Phenyl 149 2 CH₂CH₃ CH₂CH₃ 2-Br-Phenyl 150 3 CH₂CH₃CH₂CH₃ 2-Br-Phenyl 151 1 CH₃ CH₃ 3-Br-Phenyl 152 2 CH₃ CH₃ 3-Br-Phenyl153 3 CH₃ CH₃ 3-Br-Phenyl 154 1 CH₂CH₃ CH₂CH₃ 3-Br-Phenyl 155 2 CH₂CH₃CH₂CH₃ 3-Br-Phenyl 156 3 CH₂CH₃ CH₂CH₃ 3-Br-Phenyl 157 1 CH₃ CH₃2,3-di-CH₃-phenyl 158 2 CH₃ CH₃ 2,3-di-CH₃-phenyl 159 3 CH₃ CH₃2,3-di-CH₃-phenyl 160 1 CH₂CH₃ CH₂CH₃ 2,3-di-CH₃-phenyl 161 2 CH₂CH₃CH₂CH₃ 2,3-di-CH₃-phenyl 162 3 CH₂CH₃ CH₂CH₃ 2,3-di-CH₃-phenyl 163 1 CH₃CH₃ 2,4-di-CH₃-phenyl 164 2 CH₃ CH₃ 2,4-di-CH₃-phenyl 165 3 CH₃ CH₃2,4-di-CH₃-phenyl 166 1 CH₂CH₃ CH₂CH₃ 2,4-di-CH₃-phenyl 167 2 CH₂CH₃CH₂CH₃ 2,4-di-CH₃-phenyl 168 3 CH₂CH₃ CH₂CH₃ 2,4-di-CH₃-phenyl 169 1 CH₃CH₃ 2,5-di-CH₃-phenyl 170 2 CH₃ CH₃ 2,5-di-CH₃-phenyl 171 3 CH₃ CH₃2,5-di-CH₃-phenyl 172 1 CH₂CH₃ CH₂CH₃ 2,5-di-CH₃-phenyl 173 2 CH₂CH₃CH₂CH₃ 2,5-di-CH₃-phenyl 174 3 CH₂CH₃ CH₂CH₃ 2,5-di-CH₃-phenyl 175 1 CH₃CH₃ 2,6-di-CH₃-phenyl 176 2 CH₃ CH₃ 2,6-di-CH₃-phenyl 177 3 CH₃ CH₃2,6-di-CH₃-phenyl 178 1 CH₂CH₃ CH₂CH₃ 2,6-di-CH₃-phenyl 179 2 CH₂CH₃CH₂CH₃ 2,6-di-CH₃-phenyl 180 3 CH₂CH₃ CH₂CH₃ 2,6-di-CH₃-phenyl 181 1 CH₃CH₃ 3,4-di-CH₃-phenyl 182 2 CH₃ CH₃ 3,4-di-CH₃-phenyl 183 3 CH₃ CH₃3,4-di-CH₃-phenyl 184 1 CH₂CH₃ CH₂CH₃ 3,4-di-CH₃-phenyl 185 2 CH₂CH₃CH₂CH₃ 3,4-di-CH₃-phenyl 186 3 CH₂CH₃ CH₂CH₃ 3,4-di-CH₃-phenyl 187 1 CH₃CH₃ 3,5-di-CH₃-phenyl 188 2 CH₃ CH₃ 3,5-di-CH₃-phenyl 189 3 CH₃ CH₃3,5-di-CH₃-phenyl 190 1 CH₂CH₃ CH₂CH₃ 3,5-di-CH₃-phenyl 191 2 CH₂CH₃CH₂CH₃ 3,5-di-CH₃-phenyl 192 3 CH₂CH₃ CH₂CH₃ 3,5-di-CH₃-phenyl 193 1 CH₃CH₃ 2,3-di-Cl-phenyl 194 2 CH₃ CH₃ 2,3-di-Cl-phenyl 195 3 CH₃ CH₃2,3-di-Cl-phenyl 196 1 CH₂CH₃ CH₂CH₃ 2,3-di-Cl-phenyl 197 2 CH₂CH₃CH₂CH₃ 2,3-di-Cl-phenyl 198 3 CH₂CH₃ CH₂CH₃ 2,3-di-Cl-phenyl 199 1 CH₃CH₃ 2,4-di-Cl-phenyl 200 2 CH₃ CH₃ 2,4-di-Cl-phenyl 201 3 CH₃ CH₃2,4-di-Cl-phenyl 202 1 CH₂CH₃ CH₂CH₃ 2,4-di-Cl-phenyl 203 2 CH₂CH₃CH₂CH₃ 2,4-di-Cl-phenyl 204 3 CH₂CH₃ CH₂CH₃ 2,4-di-Cl-phenyl 205 1 CH₃CH₃ 2,5-di-Cl-phenyl 206 2 CH₃ CH₃ 2,5-di-Cl-phenyl 207 3 CH₃ CH₃2,5-di-Cl-phenyl 280 1 CH₂CH₃ CH₂CH₃ 2,5-di-Cl-phenyl 209 2 CH₂CH₃CH₂CH₃ 2,5-di-Cl-phenyl 210 3 CH₂CH₃ CH₂CH₃ 2,5-di-Cl-phenyl 211 1 CH₃CH₃ 2,6-di-Cl-phenyl 212 2 CH₃ CH₃ 2,6-di-Cl-phenyl 213 3 CH₃ CH₃2,6-di-Cl-phenyl 214 1 CH₂CH₃ CH₂CH₃ 2,6-di-Cl-phenyl 215 2 CH₂CH₃CH₂CH₃ 2,6-di-Cl-phenyl 216 3 CH₂CH₃ CH₂CH₃ 2,6-di-Cl-phenyl 217 1 CH₃CH₃ 3,4-di-Cl-phenyl 218 2 CH₃ CH₃ 3,4-di-Cl-phenyl 219 3 CH₃ CH₃3,4-di-Cl-phenyl 220 1 CH₂CH₃ CH₂CH₃ 3,4-di-Cl-phenyl 221 2 CH₂CH₃CH₂CH₃ 3,4-di-Cl-phenyl 222 3 CH₂CH₃ CH₂CH₃ 3,4-di-Cl-phenyl 223 1 CH₃CH₃ 3,5-di-Cl-phenyl 224 2 CH₃ CH₃ 3,5-di-Cl-phenyl 225 3 CH₃ CH₃3,5-di-Cl-phenyl 226 1 CH₂CH₃ CH₂CH₃ 3,5-di-Cl-phenyl 227 2 CH₂CH₃CH₂CH₃ 3,5-di-Cl-phenyl 228 3 CH₂CH₃ CH₂CH₃ 3,5-di-Cl-phenyl 229 1 CH₃CH₃ 2-morpholino-4-CH₃-phenyl 230 2 CH₃ CH₃ 2-morpholino-4-CH₃-phenyl231 3 CH₃ CH₃ 2-morpholino-4-CH₃-phenyl 232 1 CH₂CH₃ CH₂CH₃2-morpholino-4-CH₃-phenyl 233 2 CH₂CH₃ CH₂CH₃ 2-morpholino-4-CH₃-phenyl234 3 CH₂CH₃ CH₂CH₃ 2-morpholino-4-CH₃-phenyl 235 1 CH₃ CH₃2-morpholino-4-CN-phenyl 236 2 CH₃ CH₃ 2-morpholino-4-CN-phenyl 237 3CH₃ CH₃ 2-morpholino-4-CN-phenyl 238 1 CH₂CH₃ CH₂CH₃2-morpholino-4-CN-phenyl 239 2 CH₂CH₃ CH₂CH₃ 2-morpholino-4-CN-phenyl240 3 CH₂CH₃ CH₂CH₃ 2-morpholino-4-CN-phenyl 241 1 CH₃ CH₃2-morpholino-4-OH-phenyl 242 2 CH₃ CH₃ 2-morpholino-4-OH-phenyl 243 3CH₃ CH₃ 2-morpholino-4-OH-phenyl 244 1 CH₂CH₃ CH₂CH₃2-morpholino-4-OH-phenyl 245 2 CH₂CH₃ CH₂CH₃ 2-morpholino-4-OH-phenyl246 3 CH₂CH₃ CH₂CH₃ 2-morpholino-4-OH-phenyl 247 1 CH₃ CH₃2,3-dimethylpyridin-4-yl 248 2 CH₃ CH₃ 2,3-dimethylpyridin-4-yl 249 3CH₃ CH₃ 2,3-dimethylpyridin-4-yl 250 1 CH₂CH₃ CH₂CH₃2,3-dimethylpyridin-4-yl 251 2 CH₂CH₃ CH₂CH₃ 2,3-dimethylpyridin-4-yl252 3 CH₂CH₃ CH₂CH₃ 2,3-dimethylpyridin-4-yl 253 1 CH₃ CH₃3,6-dimethylpyridin-4-yl 254 2 CH₃ CH₃ 3,6-dimethylpyridin-4-yl 255 3CH₃ CH₃ 3,6-dimethylpyridin-4-yl 256 1 CH₂CH₃ CH₂CH₃3,6-dimethylpyridin-4-yl 257 2 CH₂CH₃ CH₂CH₃ 3,6-dimethylpyridin-4-yl258 3 CH₂CH₃ CH₂CH₃ 3,6-dimethylpyridin-4-yl

Exemplary embodiments include compounds having the formula (X) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 12.

TABLE 12 Entry n R² Entry n R² 1 1 2-CF₃-Phenyl 67 1 3-CONH₂-Phenyl 2 22-CF₃-Phenyl 68 2 3-CONH₂-Phenyl 3 3 2-CF₃-Phenyl 69 3 3-CONH₂-Phenyl 41 3-CF₃-Phenyl 70 1 4-CONH₂-Phenyl 5 2 3-CF₃-Phenyl 71 2 4-CONH₂-Phenyl6 3 3-CF₃-Phenyl 72 3 4-CONH₂-Phenyl 7 1 4-CF₃-Phenyl 73 1 2-Br-Phenyl 82 4-CF₃-Phenyl 74 2 2-Br-Phenyl 9 3 4-CF₃-Phenyl 75 3 2-Br-Phenyl 10 12-NH₂-Phenyl 76 1 3-Br-Phenyl 11 2 2-NH₂-Phenyl 77 2 3-Br-Phenyl 12 32-NH₂-Phenyl 78 3 3-Br-Phenyl 13 1 3-NH₂-Phenyl 79 1 2,3-di-CH₃-phenyl14 2 3-NH₂-Phenyl 80 2 2,3-di-CH₃-phenyl 15 3 3-NH₂-Phenyl 81 32,3-di-CH₃-phenyl 16 1 4-NH₂-Phenyl 82 1 2,4-di-CH₃-phenyl 17 24-NH₂-Phenyl 83 2 2,4-di-CH₃-phenyl 18 3 4-NH₂-Phenyl 84 32,4-di-CH₃-phenyl 19 1 2-tBu-Phenyl 85 1 2,5-di-CH₃-phenyl 20 22-tBu-Phenyl 86 2 2,5-di-CH₃-phenyl 21 3 2-tBu-Phenyl 87 32,5-di-CH₃-phenyl 22 1 3-tBu-Phenyl 88 1 2,6-di-CH₃-phenyl 23 23-tBu-Phenyl 89 2 2,6-di-CH₃-phenyl 24 3 3-tBu-Phenyl 90 32,6-di-CH₃-phenyl 25 1 4-tBu-Phenyl 91 1 3,4-di-CH₃-phenyl 26 24-tBu-Phenyl 92 2 3,4-di-CH₃-phenyl 27 3 4-tBu-Phenyl 93 33,4-di-CH₃-phenyl 28 1 2-NO₂-Phenyl 94 1 3,5-di-CH₃-phenyl 29 22-NO₂-Phenyl 95 2 3,5-di-CH₃-phenyl 30 3 2-NO₂-Phenyl 96 33,5-di-CH₃-phenyl 31 1 3-NO₂-Phenyl 97 1 2,3-di-Cl-phenyl 32 23-NO₂-Phenyl 98 2 2,3-di-Cl-phenyl 33 3 3-NO₂-Phenyl 99 32,3-di-Cl-phenyl 34 1 4-NO₂-Phenyl 100 1 2,4-di-Cl-phenyl 35 24-NO₂-Phenyl 101 2 2,4-di-Cl-phenyl 36 3 4-NO₂-Phenyl 102 32,4-di-Cl-phenyl 37 1 2-SCH₃-Phenyl 103 1 2,5-di-Cl-phenyl 38 22-SCH₃-Phenyl 104 2 2,5-di-Cl-phenyl 39 3 2-SCH₃-Phenyl 105 32,5-di-Cl-phenyl 40 1 3-SCH₃-Phenyl 106 1 2,6-di-Cl-phenyl 41 23-SCH₃-Phenyl 107 2 2,6-di-Cl-phenyl 42 3 3-SCH₃-Phenyl 108 32,6-di-Cl-phenyl 43 1 4-SCH₃-Phenyl 109 1 3,4-di-Cl-phenyl 44 24-SCH₃-Phenyl 110 2 3,4-di-Cl-phenyl 45 3 4-SCH₃-Phenyl 111 33,4-di-Cl-phenyl 46 1 2-SO₂CH₃-Phenyl 112 1 3,5-di-Cl-phenyl 47 22-SO₂CH₃-Phenyl 113 2 3,5-di-Cl-phenyl 48 3 2-SO₂CH₃-Phenyl 114 33,5-di-Cl-phenyl 49 1 3-SO₂CH₃-Phenyl 115 1 2-morpholino-4-CH₃-phenyl 502 3-SO₂CH₃-Phenyl 116 2 2-morpholino-4-CH₃-phenyl 51 3 3-SO₂CH₃-Phenyl117 3 2-morpholino-4-CH₃-phenyl 52 1 4-SO₂CH₃-Phenyl 118 12-morpholino-4-CN-phenyl 53 2 4-SO₂CH₃-Phenyl 119 22-morpholino-4-CN-phenyl 54 3 4-SO₂CH₃-Phenyl 120 32-morpholino-4-CN-phenyl 55 1 2-SO₂NH₂-Phenyl 121 12-morpholino-4-OH-phenyl 56 2 2-SO₂NH₂-Phenyl 122 22-morpholino-4-OH-phenyl 57 3 2-SO₂NH₂-Phenyl 123 32-morpholino-4-OH-phenyl 58 1 3-SO₂NH₂-Phenyl 124 12,3-dimethylpyridin-4-yl 59 2 3-SO₂NH₂-Phenyl 125 22,3-dimethylpyridin-4-yl 60 3 3-SO₂NH₂-Phenyl 126 32,3-dimethylpyridin-4-yl 61 1 4-SO₂NH₂-Phenyl 127 13,6-dimethylpyridin-4-yl 62 2 4-SO₂NH₂-Phenyl 128 23,6-dimethylpyridin-4-yl 63 3 4-SO₂NH₂-Phenyl 129 33,6-dimethylpyridin-4-yl 64 1 2-CONH₂-Phenyl 65 2 2-CONH₂-Phenyl 66 32-CONH₂-Phenyl

Exemplary embodiments include compounds having the formula (XI) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R and n are defined herein below inTable 13.

TABLE 13 Entry n R² Entry n R² 1 1 2-CF₃-Phenyl 67 1 3-CONH₂-Phenyl 2 22-CF₃-Phenyl 68 2 3-CONH₂-Phenyl 3 3 2-CF₃-Phenyl 69 3 3-CONH₂-Phenyl 41 3-CF₃-Phenyl 70 1 4-CONH₂-Phenyl 5 2 3-CF₃-Phenyl 71 2 4-CONH₂-Phenyl6 3 3-CF₃-Phenyl 72 3 4-CONH₂-Phenyl 7 1 4-CF₃-Phenyl 73 1 2-Br-Phenyl 82 4-CF₃-Phenyl 74 2 2-Br-Phenyl 9 3 4-CF₃-Phenyl 75 3 2-Br-Phenyl 10 12-NH₂-Phenyl 76 1 3-Br-Phenyl 11 2 2-NH₂-Phenyl 77 2 3-Br-Phenyl 12 32-NH₂-Phenyl 78 3 3-Br-Phenyl 13 1 3-NH₂-Phenyl 79 1 2,3-di-CH₃-phenyl14 2 3-NH₂-Phenyl 80 2 2,3-di-CH₃-phenyl 15 3 3-NH₂-Phenyl 81 32,3-di-CH₃-phenyl 16 1 4-NH₂-Phenyl 82 1 2,4-di-CH₃-phenyl 17 24-NH₂-Phenyl 83 2 2,4-di-CH₃-phenyl 18 3 4-NH₂-Phenyl 84 32,4-di-CH₃-phenyl 19 1 2-tBu-Phenyl 85 1 2,5-di-CH₃-phenyl 20 22-tBu-Phenyl 86 2 2,5-di-CH₃-phenyl 21 3 2-tBu-Phenyl 87 32,5-di-CH₃-phenyl 22 1 3-tBu-Phenyl 88 1 2,6-di-CH₃-phenyl 23 23-tBu-Phenyl 89 2 2,6-di-CH₃-phenyl 24 3 3-tBu-Phenyl 90 32,6-di-CH₃-phenyl 25 1 4-tBu-Phenyl 91 1 3,4-di-CH₃-phenyl 26 24-tBu-Phenyl 92 2 3,4-di-CH₃-phenyl 27 3 4-tBu-Phenyl 93 33,4-di-CH₃-phenyl 28 1 2-NO₂-Phenyl 94 1 3,5-di-CH₃-phenyl 29 22-NO₂-Phenyl 95 2 3,5-di-CH₃-phenyl 30 3 2-NO₂-Phenyl 96 33,5-di-CH₃-phenyl 31 1 3-NO₂-Phenyl 97 1 2,3-di-Cl-phenyl 32 23-NO₂-Phenyl 98 2 2,3-di-Cl-phenyl 33 3 3-NO₂-Phenyl 99 32,3-di-Cl-phenyl 34 1 4-NO₂-Phenyl 100 1 2,4-di-Cl-phenyl 35 24-NO₂-Phenyl 101 2 2,4-di-Cl-phenyl 36 3 4-NO₂-Phenyl 102 32,4-di-Cl-phenyl 37 1 2-SCH₃-Phenyl 103 1 2,5-di-Cl-phenyl 38 22-SCH₃-Phenyl 104 2 2,5-di-Cl-phenyl 39 3 2-SCH₃-Phenyl 105 32,5-di-Cl-phenyl 40 1 3-SCH₃-Phenyl 106 1 2,6-di-Cl-phenyl 41 23-SCH₃-Phenyl 107 2 2,6-di-Cl-phenyl 42 3 3-SCH₃-Phenyl 108 32,6-di-Cl-phenyl 43 1 4-SCH₃-Phenyl 109 1 3,4-di-Cl-phenyl 44 24-SCH₃-Phenyl 110 2 3,4-di-Cl-phenyl 45 3 4-SCH₃-Phenyl 111 33,4-di-Cl-phenyl 46 1 2-SO₂CH₃-Phenyl 112 1 3,5-di-Cl-phenyl 47 22-SO₂CH₃-Phenyl 113 2 3,5-di-Cl-phenyl 48 3 2-SO₂CH₃-Phenyl 114 33,5-di-Cl-phenyl 49 1 3-SO₂CH₃-Phenyl 115 1 2-morpholino-4-CH₃-phenyl 502 3-SO₂CH₃-Phenyl 116 2 2-morpholino-4-CH₃-phenyl 51 3 3-SO₂CH₃-Phenyl117 3 2-morpholino-4-CH₃-phenyl 52 1 4-SO₂CH₃-Phenyl 118 12-morpholino-4-CN-phenyl 53 2 4-SO₂CH₃-Phenyl 119 22-morpholino-4-CN-phenyl 54 3 4-SO₂CH₃-Phenyl 120 32-morpholino-4-CN-phenyl 55 1 2-SO₂NH₂-Phenyl 121 12-morpholino-4-OH-phenyl 56 2 2-SO₂NH₂-Phenyl 122 22-morpholino-4-OH-phenyl 57 3 2-SO₂NH₂-Phenyl 123 32-morpholino-4-OH-phenyl 58 1 3-SO₂NH₂-Phenyl 124 12,3-dimethylpyridin-4-yl 59 2 3-SO₂NH₂-Phenyl 125 22,3-dimethylpyridin-4-yl 60 3 3-SO₂NH₂-Phenyl 126 32,3-dimethylpyridin-4-yl 61 1 4-SO₂NH₂-Phenyl 127 13,6-dimethylpyridin-4-yl 62 2 4-SO₂NH₂-Phenyl 128 23,6-dimethylpyridin-4-yl 63 3 4-SO₂NH₂-Phenyl 129 33,6-dimethylpyridin-4-yl 64 1 2-CONH₂-Phenyl 65 2 2-CONH₂-Phenyl 66 32-CONH₂-Phenyl

Exemplary embodiments include compounds having the formula (XII) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 14.

TABLE 14 Entry n R² 1 1 2-CF₃-Phenyl 2 2 2-CF₃-Phenyl 3 3 2-CF₃-Phenyl 41 3-CF₃-Phenyl 5 2 3-CF₃-Phenyl 6 3 3-CF₃-Phenyl 7 1 4-CF₃-Phenyl 8 24-CF₃-Phenyl 9 3 4-CF₃-Phenyl 10 1 2-NH₂-Phenyl 11 2 2-NH₂-Phenyl 12 32-NH₂-Phenyl 13 1 3-NH₂-Phenyl 14 2 3-NH₂-Phenyl 15 3 3-NH₂-Phenyl 16 14-NH₂-Phenyl 17 2 4-NH₂-Phenyl 18 3 4-NH₂-Phenyl 19 1 2-tBu-Phenyl 20 22-tBu-Phenyl 21 3 2-tBu-Phenyl 22 1 3-tBu-Phenyl 23 2 3-tBu-Phenyl 24 33-tBu-Phenyl 25 1 4-tBu-Phenyl 26 2 4-tBu-Phenyl 27 3 4-tBu-Phenyl 28 12-NO₂-Phenyl 29 2 2-NO₂-Phenyl 30 3 2-NO₂-Phenyl 31 1 3-NO₂-Phenyl 32 23-NO₂-Phenyl 33 3 3-NO₂-Phenyl 34 1 4-NO₂-Phenyl 35 2 4-NO₂-Phenyl 36 34-NO₂-Phenyl 37 1 2-SCH₃-Phenyl 38 2 2-SCH₃-Phenyl 39 3 2-SCH₃-Phenyl 401 3-SCH₃-Phenyl 41 2 3-SCH₃-Phenyl 42 3 3-SCH₃-Phenyl 43 1 4-SCH₃-Phenyl44 2 4-SCH₃-Phenyl 45 3 4-SCH₃-Phenyl 46 1 2-SO₂CH₃-Phenyl 47 22-SO₂CH₃-Phenyl 48 3 2-SO₂CH₃-Phenyl 49 1 3-SO₂CH₃-Phenyl 50 23-SO₂CH₃-Phenyl 51 3 3-SO₂CH₃-Phenyl 52 1 4-SO₂CH₃-Phenyl 53 24-SO₂CH₃-Phenyl 54 3 4-SO₂CH₃-Phenyl 55 1 2-SO₂NH₂-Phenyl 56 22-SO₂NH₂-Phenyl 57 3 2-SO₂NH₂-Phenyl 58 1 3-SO₂NH₂-Phenyl 59 23-SO₂NH₂-Phenyl 60 3 3-SO₂NH₂-Phenyl 61 1 4-SO₂NH₂-Phenyl 62 24-SO₂NH₂-Phenyl 63 3 4-SO₂NH₂-Phenyl 64 1 2-CONH₂-Phenyl 65 22-CONH₂-Phenyl 66 3 2-CONH₂-Phenyl 67 1 3-CONH₂-Phenyl 68 23-CONH₂-Phenyl 69 3 3-CONH₂-Phenyl 70 1 4-CONH₂-Phenyl 71 24-CONH₂-Phenyl 72 3 4-CONH₂-Phenyl 73 1 2-Br-Phenyl 74 2 2-Br-Phenyl 753 2-Br-Phenyl 76 1 3-Br-Phenyl 77 2 3-Br-Phenyl 78 3 3-Br-Phenyl 79 12,3-di-CH₃-phenyl 80 2 2,3-di-CH₃-phenyl 81 3 2,3-di-CH₃-phenyl 82 12,4-di-CH₃-phenyl 83 2 2,4-di-CH₃-phenyl 84 3 2,4-di-CH₃-phenyl 85 12,5-di-CH₃-phenyl 86 2 2,5-di-CH₃-phenyl 87 3 2,5-di-CH₃-phenyl 88 12,6-di-CH₃-phenyl 89 2 2,6-di-CH₃-phenyl 90 3 2,6-di-CH₃-phenyl 91 13,4-di-CH₃-phenyl 92 2 3,4-di-CH₃-phenyl 93 3 3,4-di-CH₃-phenyl 94 13,5-di-CH₃-phenyl 95 2 3,5-di-CH₃-phenyl 96 3 3,5-di-CH₃-phenyl 97 12,3-di-Cl-phenyl 98 2 2,3-di-Cl-phenyl 99 3 2,3-di-Cl-phenyl 100 12,4-di-Cl-phenyl 101 2 2,4-di-Cl-phenyl 102 3 2,4-di-Cl-phenyl 103 12,5-di-Cl-phenyl 104 2 2,5-di-Cl-phenyl 105 3 2,5-di-Cl-phenyl 106 12,6-di-Cl-phenyl 107 2 2,6-di-Cl-phenyl 108 3 2,6-di-Cl-phenyl 109 13,4-di-Cl-phenyl 110 2 3,4-di-Cl-phenyl 111 3 3,4-di-Cl-phenyl 112 13,5-di-Cl-phenyl 113 2 3,5-di-Cl-phenyl 114 3 3,5-di-Cl-phenyl 115 12-morpholino-4-CH₃-phenyl 116 2 2-morpholino-4-CH₃-phenyl 117 32-morpholino-4-CH₃-phenyl 118 1 2-morpholino-4-CN-phenyl 119 22-morpholino-4-CN-phenyl 120 3 2-morpholino-4-CN-phenyl 121 12-morpholino-4-OH-phenyl 122 2 2-morpholino-4-OH-phenyl 123 32-morpholino-4-OH-phenyl 124 1 2,3-dimethylpyridin-4-yl 125 22,3-dimethylpyridin-4-yl 126 3 2,3-dimethylpyridin-4-yl 127 13,6-dimethylpyridin-4-yl 128 2 3,6-dimethylpyridin-4-yl 129 33,6-dimethylpyridin-4-yl

Exemplary embodiments include compounds having the formula (XIII) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 15.

TABLE 15 Entry n R² 1 1 2-CF₃-Phenyl 2 2 2-CF₃-Phenyl 3 3 2-CF₃-Phenyl 41 3-CF₃-Phenyl 5 2 3-CF₃-Phenyl 6 3 3-CF₃-Phenyl 7 1 4-CF₃-Phenyl 8 24-CF₃-Phenyl 9 3 4-CF₃-Phenyl 10 1 2-NH₂-Phenyl 11 2 2-NH₂-Phenyl 12 32-NH₂-Phenyl 13 1 3-NH₂-Phenyl 14 2 3-NH₂-Phenyl 15 3 3-NH₂-Phenyl 16 14-NH₂-Phenyl 17 2 4-NH₂-Phenyl 18 3 4-NH₂-Phenyl 19 1 2-tBu-Phenyl 20 22-tBu-Phenyl 21 3 2-tBu-Phenyl 22 1 3-tBu-Phenyl 23 2 3-tBu-Phenyl 24 33-tBu-Phenyl 25 1 4-tBu-Phenyl 26 2 4-tBu-Phenyl 27 3 4-tBu-Phenyl 28 12-NO₂-Phenyl 29 2 2-NO₂-Phenyl 30 3 2-NO₂-Phenyl 31 1 3-NO₂-Phenyl 32 23-NO₂-Phenyl 33 3 3-NO₂-Phenyl 34 1 4-NO₂-Phenyl 35 2 4-NO₂-Phenyl 36 34-NO₂-Phenyl 37 1 2-SCH₃-Phenyl 38 2 2-SCH₃-Phenyl 39 3 2-SCH₃-Phenyl 401 3-SCH₃-Phenyl 41 2 3-SCH₃-Phenyl 42 3 3-SCH₃-Phenyl 43 1 4-SCH₃-Phenyl44 2 4-SCH₃-Phenyl 45 3 4-SCH₃-Phenyl 46 1 2-SO₂CH₃-Phenyl 47 22-SO₂CH₃-Phenyl 48 3 2-SO₂CH₃-Phenyl 49 1 3-SO₂CH₃-Phenyl 50 23-SO₂CH₃-Phenyl 51 3 3-SO₂CH₃-Phenyl 52 1 4-SO₂CH₃-Phenyl 53 24-SO₂CH₃-Phenyl 54 3 4-SO₂CH₃-Phenyl 55 1 2-SO₂NH₂-Phenyl 56 22-SO₂NH₂-Phenyl 57 3 2-SO₂NH₂-Phenyl 58 1 3-SO₂NH₂-Phenyl 59 23-SO₂NH₂-Phenyl 60 3 3-SO₂NH₂-Phenyl 61 1 4-SO₂NH₂-Phenyl 62 24-SO₂NH₂-Phenyl 63 3 4-SO₂NH₂-Phenyl 64 1 2-CONH₂-Phenyl 65 22-CONH₂-Phenyl 66 3 2-CONH₂-Phenyl 67 1 3-CONH₂-Phenyl 68 23-CONH₂-Phenyl 69 3 3-CONH₂-Phenyl 70 1 4-CONH₂-Phenyl 71 24-CONH₂-Phenyl 72 3 4-CONH₂-Phenyl 73 1 2-Br-Phenyl 74 2 2-Br-Phenyl 753 2-Br-Phenyl 76 1 3-Br-Phenyl 77 2 3-Br-Phenyl 78 3 3-Br-Phenyl 79 12,3-di-CH₃-phenyl 80 2 2,3-di-CH₃-phenyl 81 3 2,3-di-CH₃-phenyl 82 12,4-di-CH₃-phenyl 83 2 2,4-di-CH₃-phenyl 84 3 2,4-di-CH₃-phenyl 85 12,5-di-CH₃-phenyl 86 2 2,5-di-CH₃-phenyl 87 3 2,5-di-CH₃-phenyl 88 12,6-di-CH₃-phenyl 89 2 2,6-di-CH₃-phenyl 90 3 2,6-di-CH₃-phenyl 91 13,4-di-CH₃-phenyl 92 2 3,4-di-CH₃-phenyl 93 3 3,4-di-CH₃-phenyl 94 13,5-di-CH₃-phenyl 95 2 3,5-di-CH₃-phenyl 96 3 3,5-di-CH₃-phenyl 97 12,3-di-Cl-phenyl 98 2 2,3-di-Cl-phenyl 99 3 2,3-di-Cl-phenyl 100 12,4-di-Cl-phenyl 101 2 2,4-di-Cl-phenyl 102 3 2,4-di-Cl-phenyl 103 12,5-di-Cl-phenyl 104 2 2,5-di-Cl-phenyl 105 3 2,5-di-Cl-phenyl 106 12,6-di-Cl-phenyl 107 2 2,6-di-Cl-phenyl 108 3 2,6-di-Cl-phenyl 109 13,4-di-Cl-phenyl 110 2 3,4-di-Cl-phenyl 111 3 3,4-di-Cl-phenyl 112 13,5-di-Cl-phenyl 113 2 3,5-di-Cl-phenyl 114 3 3,5-di-Cl-phenyl 115 12-morpholino-4-CH₃-phenyl 116 2 2-morpholino-4-CH₃-phenyl 117 32-morpholino-4-CH₃-phenyl 118 1 2-morpholino-4-CN-phenyl 119 22-morpholino-4-CN-phenyl 120 3 2-morpholino-4-CN-phenyl 121 12-morpholino-4-OH-phenyl 122 2 2-morpholino-4-OH-phenyl 123 32-morpholino-4-OH-phenyl 124 1 2,3-dimethylpyridin-4-yl 125 22,3-dimethylpyridin-4-yl 126 3 2,3-dimethylpyridin-4-yl 127 13,6-dimethylpyridin-4-yl 128 2 3,6-dimethylpyridin-4-yl 129 33,6-dimethylpyridin-4-yl

Exemplary embodiments include compounds having the formula (VI) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R^(1a), R^(1b), R³ and n are definedherein below in Table 16.

TABLE 16 Entry n R^(1a) R^(1b) R² 1 1 CH₃ CH₃ 2-CF₃-Phenyl 2 2 CH₃ CH₃2-CF₃-Phenyl 3 3 CH₃ CH₃ 2-CF₃-Phenyl 4 1 CH₂CH₃ CH2CH3 2-CF₃-Phenyl 5 2CH₂CH₃ CH2CH3 2-CF₃-Phenyl 6 3 CH₂CH₃ CH2CH3 2-CF₃-Phenyl 7 1 CH₃ CH₃3-CF₃-Phenyl 8 2 CH₃ CH₃ 3-CF₃-Phenyl 9 3 CH₃ CH₃ 3-CF₃-Phenyl 10 1CH₂CH₃ CH₂CH₃ 3-CF₃-Phenyl 11 2 CH₂CH₃ CH₂CH₃ 3-CF₃-Phenyl 12 3 CH₂CH₃CH₂CH₃ 3-CF₃-Phenyl 13 1 CH₃ CH₃ 4-CF₃-Phenyl 14 2 CH₃ CH₃ 4-CF₃-Phenyl15 3 CH₃ CH₃ 4-CF₃-Phenyl 16 1 CH₂CH₃ CH₂CH₃ 4-CF₃-Phenyl 17 2 CH₂CH₃CH₂CH₃ 4-CF₃-Phenyl 18 3 CH₂CH₃ CH₂CH₃ 4-CF₃-Phenyl 19 1 CH₃ CH₃2-NH₂-Phenyl 20 2 CH₃ CH₃ 2-NH₂-Phenyl 21 3 CH₃ CH₃ 2-NH₂-Phenyl 22 1CH₂CH₃ CH₂CH₃ 2-NH₂-Phenyl 23 2 CH₂CH₃ CH₂CH₃ 2-NH₂-Phenyl 24 3 CH₂CH₃CH₂CH₃ 2-NH₂-Phenyl 25 1 CH₃ CH₃ 3-NH₂-Phenyl 26 2 CH₃ CH₃ 3-NH₂-Phenyl27 3 CH₃ CH₃ 3-NH₂-Phenyl 28 1 CH₂CH₃ CH₂CH₃ 3-NH₂-Phenyl 29 2 CH₂CH₃CH₂CH₃ 3-NH₂-Phenyl 30 3 CH₂CH₃ CH₂CH₃ 3-NH₂-Phenyl 31 1 CH₃ CH₃4-NH₂-Phenyl 32 2 CH₃ CH₃ 4-NH₂-Phenyl 33 3 CH₃ CH₃ 4-NH₂-Phenyl 34 1CH₂CH₃ CH₂CH₃ 4-NH₂-Phenyl 35 2 CH₂CH₃ CH₂CH₃ 4-NH₂-Phenyl 36 3 CH₂CH₃CH₂CH₃ 4-NH₂-Phenyl 37 1 CH₃ CH₃ 2-tBu-Phenyl 38 2 CH₃ CH₃ 2-tBu-Phenyl39 3 CH₃ CH₃ 2-tBu-Phenyl 40 1 CH₂CH₃ CH₂CH₃ 2-tBu-Phenyl 41 2 CH₂CH₃CH₂CH₃ 2-tBu-Phenyl 42 3 CH₂CH₃ CH₂CH₃ 2-tBu-Phenyl 43 1 CH₃ CH₃3-tBu-Phenyl 44 2 CH₃ CH₃ 3-tBu-Phenyl 45 3 CH₃ CH₃ 3-tBu-Phenyl 46 1CH₂CH₃ CH₂CH₃ 3-tBu-Phenyl 47 2 CH₂CH₃ CH₂CH₃ 3-tBu-Phenyl 48 3 CH₂CH₃CH₂CH₃ 3-tBu-Phenyl 49 1 CH₃ CH₃ 4-tBu-Phenyl 50 2 CH₃ CH₃ 4-tBu-Phenyl51 3 CH₃ CH₃ 4-tBu-Phenyl 52 1 CH₂CH₃ CH₂CH₃ 4-tBu-Phenyl 53 2 CH₂CH₃CH₂CH₃ 4-tBu-Phenyl 54 3 CH₂CH₃ CH₂CH₃ 4-tBu-Phenyl 55 1 CH₃ CH₃2-NO₂-Phenyl 56 2 CH₃ CH₃ 2-NO₂-Phenyl 57 3 CH₃ CH₃ 2-NO₂-Phenyl 58 1CH₂CH₃ CH₂CH₃ 2-NO₂-Phenyl 59 2 CH₂CH₃ CH₂CH₃ 2-NO₂-Phenyl 60 3 CH₂CH₃CH₂CH₃ 2-NO₂-Phenyl 61 1 CH₃ CH₃ 3-NO₂-Phenyl 62 2 CH₃ CH₃ 3-NO₂-Phenyl63 3 CH₃ CH₃ 3-NO₂-Phenyl 64 1 CH₂CH₃ CH₂CH₃ 3-NO₂-Phenyl 65 2 CH₂CH₃CH₂CH₃ 3-NO₂-Phenyl 66 3 CH₂CH₃ CH₂CH₃ 3-NO₂-Phenyl 67 1 CH₃ CH₃4-NO₂-Phenyl 68 2 CH₃ CH₃ 4-NO₂-Phenyl 69 3 CH₃ CH₃ 4-NO₂-Phenyl 70 1CH₂CH₃ CH₂CH₃ 4-NO₂-Phenyl 71 2 CH₂CH₃ CH₂CH₃ 4-NO₂-Phenyl 72 3 CH₂CH₃CH₂CH₃ 4-NO₂-Phenyl 73 1 CH₃ CH₃ 2-SCH₃-Phenyl 74 2 CH₃ CH₃2-SCH₃-Phenyl 75 3 CH₃ CH₃ 2-SCH₃-Phenyl 76 1 CH₂CH₃ CH₂CH₃2-SCH₃-Phenyl 77 2 CH₂CH₃ CH₂CH₃ 2-SCH₃-Phenyl 78 3 CH₂CH₃ CH₂CH₃2-SCH₃-Phenyl 79 1 CH₃ CH₃ 3-SCH₃-Phenyl 80 2 CH₃ CH₃ 3-SCH₃-Phenyl 81 3CH₃ CH₃ 3-SCH₃-Phenyl 82 1 CH₂CH₃ CH₂CH₃ 3-SCH₃-Phenyl 83 2 CH₂CH₃CH₂CH₃ 3-SCH₃-Phenyl 84 3 CH₂CH₃ CH₂CH₃ 3-SCH₃-Phenyl 85 1 CH₃ CH₃4-SCH₃-Phenyl 86 2 CH₃ CH₃ 4-SCH₃-Phenyl 87 3 CH₃ CH₃ 4-SCH₃-Phenyl 88 1CH₂CH₃ CH₂CH₃ 4-SCH₃-Phenyl 89 2 CH₂CH₃ CH₂CH₃ 4-SCH₃-Phenyl 90 3 CH₂CH₃CH₂CH₃ 4-SCH₃-Phenyl 91 1 CH₃ CH₃ 2-SO₂CH₃-Phenyl 92 2 CH₃ CH₃2-SO₂CH₃-Phenyl 93 3 CH₃ CH₃ 2-SO₂CH₃-Phenyl 94 1 CH₂CH₃ CH₂CH₃2-SO₂CH₃-Phenyl 95 2 CH₂CH₃ CH₂CH₃ 2-SO₂CH₃-Phenyl 96 3 CH₂CH₃ CH₂CH₃2-SO₂CH₃-Phenyl 97 1 CH₃ CH₃ 3-SO₂CH₃-Phenyl 98 2 CH₃ CH₃3-SO₂CH₃-Phenyl 99 3 CH₃ CH₃ 3-SO₂CH₃-Phenyl 100 1 CH₂CH₃ CH₂CH₃3-SO₂CH₃-Phenyl 101 2 CH₂CH₃ CH₂CH₃ 3-SO₂CH₃-Phenyl 102 3 CH₂CH₃ CH₂CH₃3-SO₂CH₃-Phenyl 103 1 CH₃ CH₃ 4-SO₂CH₃-Phenyl 104 2 CH₃ CH₃4-SO₂CH₃-Phenyl 105 3 CH₃ CH₃ 4-SO₂CH₃-Phenyl 106 1 CH₂CH₃ CH₂CH₃4-SO₂CH₃-Phenyl 107 2 CH₂CH₃ CH₂CH₃ 4-SO₂CH₃-Phenyl 108 3 CH₂CH₃ CH₂CH₃4-SO₂CH₃-Phenyl 109 1 CH₃ CH₃ 2-SO₂NH₂-Phenyl 110 2 CH₃ CH₃2-SO₂NH₂-Phenyl 111 3 CH₃ CH₃ 2-SO₂NH₂-Phenyl 112 1 CH₂CH₃ CH₂CH₃2-SO₂NH₂-Phenyl 113 2 CH₂CH₃ CH₂CH₃ 2-SO₂NH₂-Phenyl 114 3 CH₂CH₃ CH₂CH₃2-SO₂NH₂-Phenyl 115 1 CH₃ CH₃ 3-SO₂NH₂-Phenyl 116 2 CH₃ CH₃3-SO₂NH₂-Phenyl 117 3 CH₃ CH₃ 3-SO₂NH₂-Phenyl 118 1 CH₂CH₃ CH₂CH₃3-SO₂NH₂-Phenyl 119 2 CH₂CH₃ CH₂CH₃ 3-SO₂NH₂-Phenyl 120 3 CH₂CH₃ CH₂CH₃3-SO₂NH₂-Phenyl 121 1 CH₃ CH₃ 4-SO₂NH₂-Phenyl 122 2 CH₃ CH₃4-SO₂NH₂-Phenyl 123 3 CH₃ CH₃ 4-SO₂NH₂-Phenyl 124 1 CH₂CH₃ CH₂CH₃4-SO₂NH₂-Phenyl 125 2 CH₂CH₃ CH₂CH₃ 4-SO₂NH₂-Phenyl 126 3 CH₂CH₃ CH₂CH₃4-SO₂NH₂-Phenyl 127 1 CH₃ CH₃ 2-CONH₂-Phenyl 128 2 CH₃ CH₃2-CONH₂-Phenyl 129 3 CH₃ CH₃ 2-CONH₂-Phenyl 130 1 CH₂CH₃ CH₂CH₃2-CONH₂-Phenyl 131 2 CH₂CH₃ CH₂CH₃ 2-CONH₂-Phenyl 132 3 CH₂CH₃ CH₂CH₃2-CONH₂-Phenyl 133 1 CH₃ CH₃ 3-CONH₂-Phenyl 134 2 CH₃ CH₃ 3-CONH₂-Phenyl135 3 CH₃ CH₃ 3-CONH₂-Phenyl 136 1 CH₂CH₃ CH₂CH₃ 3-CONH₂-Phenyl 137 2CH₂CH₃ CH₂CH₃ 3-CONH₂-Phenyl 138 3 CH₂CH₃ CH₂CH₃ 3-CONH₂-Phenyl 139 1CH₃ CH₃ 4-CONH₂-Phenyl 140 2 CH₃ CH₃ 4-CONH₂-Phenyl 141 3 CH₃ CH₃4-CONH₂-Phenyl 142 1 CH₂CH₃ CH₂CH₃ 4-CONH₂-Phenyl 143 2 CH₂CH₃ CH₂CH₃4-CONH₂-Phenyl 144 3 CH₂CH₃ CH₂CH₃ 4-CONH₂-Phenyl 145 1 CH₃ CH₃2-Br-Phenyl 146 2 CH₃ CH₃ 2-Br-Phenyl 147 3 CH₃ CH₃ 2-Br-Phenyl 148 1CH₂CH₃ CH₂CH₃ 2-Br-Phenyl 149 2 CH₂CH₃ CH₂CH₃ 2-Br-Phenyl 150 3 CH₂CH₃CH₂CH₃ 2-Br-Phenyl 151 1 CH₃ CH₃ 3-Br-Phenyl 152 2 CH₃ CH₃ 3-Br-Phenyl153 3 CH₃ CH₃ 3-Br-Phenyl 154 1 CH₂CH₃ CH₂CH₃ 3-Br-Phenyl 155 2 CH₂CH₃CH₂CH₃ 3-Br-Phenyl 156 3 CH₂CH₃ CH₂CH₃ 3-Br-Phenyl 157 1 CH₃ CH₃2,3-di-CH₃-phenyl 158 2 CH₃ CH₃ 2,3-di-CH₃-phenyl 159 3 CH₃ CH₃2,3-di-CH₃-phenyl 160 1 CH₂CH₃ CH₂CH₃ 2,3-di-CH₃-phenyl 161 2 CH₂CH₃CH₂CH₃ 2,3-di-CH₃-phenyl 162 3 CH₂CH₃ CH₂CH₃ 2,3-di-CH₃-phenyl 163 1 CH₃CH₃ 2,4-di-CH₃-phenyl 164 2 CH₃ CH₃ 2,4-di-CH₃-phenyl 165 3 CH₃ CH₃2,4-di-CH₃-phenyl 166 1 CH₂CH₃ CH₂CH₃ 2,4-di-CH₃-phenyl 167 2 CH₂CH₃CH₂CH₃ 2,4-di-CH₃-phenyl 168 3 CH₂CH₃ CH₂CH₃ 2,4-di-CH₃-phenyl 169 1 CH₃CH₃ 2,5-di-CH₃-phenyl 170 2 CH₃ CH₃ 2,5-di-CH₃-phenyl 171 3 CH₃ CH₃2,5-di-CH₃-phenyl 172 1 CH₂CH₃ CH₂CH₃ 2,5-di-CH₃-phenyl 173 2 CH₂CH₃CH₂CH₃ 2,5-di-CH₃-phenyl 174 3 CH₂CH₃ CH₂CH₃ 2,5-di-CH₃-phenyl 175 1 CH₃CH₃ 2,6-di-CH₃-phenyl 176 2 CH₃ CH₃ 2,6-di-CH₃-phenyl 177 3 CH₃ CH₃2,6-di-CH₃-phenyl 178 1 CH₂CH₃ CH₂CH₃ 2,6-di-CH₃-phenyl 179 2 CH₂CH₃CH₂CH₃ 2,6-di-CH₃-phenyl 180 3 CH₂CH₃ CH₂CH₃ 2,6-di-CH₃-phenyl 181 1 CH₃CH₃ 3,4-di-CH₃-phenyl 182 2 CH₃ CH₃ 3,4-di-CH₃-phenyl 183 3 CH₃ CH₃3,4-di-CH₃-phenyl 184 1 CH₂CH₃ CH₂CH₃ 3,4-di-CH₃-phenyl 185 2 CH₂CH₃CH₂CH₃ 3,4-di-CH₃-phenyl 186 3 CH₂CH₃ CH₂CH₃ 3,4-di-CH₃-phenyl 187 1 CH₃CH₃ 3,5-di-CH₃-phenyl 188 2 CH₃ CH₃ 3,5-di-CH₃-phenyl 189 3 CH₃ CH₃3,5-di-CH₃-phenyl 190 1 CH₂CH₃ CH₂CH₃ 3,5-di-CH₃-phenyl 191 2 CH₂CH₃CH₂CH₃ 3,5-di-CH₃-phenyl 192 3 CH₂CH₃ CH₂CH₃ 3,5-di-CH₃-phenyl 193 1 CH₃CH₃ 2,3-di-Cl-phenyl 194 2 CH₃ CH₃ 2,3-di-Cl-phenyl 195 3 CH₃ CH₃2,3-di-Cl-phenyl 196 1 CH₂CH₃ CH₂CH₃ 2,3-di-Cl-phenyl 197 2 CH₂CH₃CH₂CH₃ 2,3-di-Cl-phenyl 198 3 CH₂CH₃ CH₂CH₃ 2,3-di-Cl-phenyl 199 1 CH₃CH₃ 2,4-di-Cl-phenyl 200 2 CH₃ CH₃ 2,4-di-Cl-phenyl 201 3 CH₃ CH₃2,4-di-Cl-phenyl 202 1 CH₂CH₃ CH₂CH₃ 2,4-di-Cl-phenyl 203 2 CH₂CH₃CH₂CH₃ 2,4-di-Cl-phenyl 204 3 CH₂CH₃ CH₂CH₃ 2,4-di-Cl-phenyl 205 1 CH₃CH₃ 2,5-di-Cl-phenyl 206 2 CH₃ CH₃ 2,5-di-Cl-phenyl 207 3 CH₃ CH₃2,5-di-Cl-phenyl 280 1 CH₂CH₃ CH₂CH₃ 2,5-di-Cl-phenyl 209 2 CH₂CH₃CH₂CH₃ 2,5-di-Cl-phenyl 210 3 CH₂CH₃ CH₂CH₃ 2,5-di-Cl-phenyl 211 1 CH₃CH₃ 2,6-di-Cl-phenyl 212 2 CH₃ CH₃ 2,6-di-Cl-phenyl 213 3 CH₃ CH₃2,6-di-Cl-phenyl 214 1 CH₂CH₃ CH₂CH₃ 2,6-di-Cl-phenyl 215 2 CH₂CH₃CH₂CH₃ 2,6-di-Cl-phenyl 216 3 CH₂CH₃ CH₂CH₃ 2,6-di-Cl-phenyl 217 1 CH₃CH₃ 3,4-di-Cl-phenyl 218 2 CH₃ CH₃ 3,4-di-Cl-phenyl 219 3 CH₃ CH₃3,4-di-Cl-phenyl 220 1 CH₂CH₃ CH₂CH₃ 3,4-di-Cl-phenyl 221 2 CH₂CH₃CH₂CH₃ 3,4-di-Cl-phenyl 222 3 CH₂CH₃ CH₂CH₃ 3,4-di-Cl-phenyl 223 1 CH₃CH₃ 3,5-di-Cl-phenyl 224 2 CH₃ CH₃ 3,5-di-Cl-phenyl 225 3 CH₃ CH₃3,5-di-Cl-phenyl 226 1 CH₂CH₃ CH₂CH₃ 3,5-di-Cl-phenyl 227 2 CH₂CH₃CH₂CH₃ 3,5-di-Cl-phenyl 228 3 CH₂CH₃ CH₂CH₃ 3,5-di-Cl-phenyl 229 1 CH₃CH₃ 2-morpholino-4-CH₃-phenyl 230 2 CH₃ CH₃ 2-morpholino-4-CH₃-phenyl231 3 CH₃ CH₃ 2-morpholino-4-CH₃-phenyl 232 1 CH₂CH₃ CH₂CH₃2-morpholino-4-CH₃-phenyl 233 2 CH₂CH₃ CH₂CH₃ 2-morpholino-4-CH₃-phenyl234 3 CH₂CH₃ CH₂CH₃ 2-morpholino-4-CH₃-phenyl 235 1 CH₃ CH₃2-morpholino-4-CN-phenyl 236 2 CH₃ CH₃ 2-morpholino-4-CN-phenyl 237 3CH₃ CH₃ 2-morpholino-4-CN-phenyl 238 1 CH₂CH₃ CH₂CH₃2-morpholino-4-CN-phenyl 239 2 CH₂CH₃ CH₂CH₃ 2-morpholino-4-CN-phenyl240 3 CH₂CH₃ CH₂CH₃ 2-morpholino-4-CN-phenyl 241 1 CH₃ CH₃2-morpholino-4-OH-phenyl 242 2 CH₃ CH₃ 2-morpholino-4-OH-phenyl 243 3CH₃ CH₃ 2-morpholino-4-OH-phenyl 244 1 CH₂CH₃ CH₂CH₃2-morpholino-4-OH-phenyl 245 2 CH₂CH₃ CH₂CH₃ 2-morpholino-4-OH-phenyl246 3 CH₂CH₃ CH₂CH₃ 2-morpholino-4-OH-phenyl 247 1 CH₃ CH₃2,3-dimethylpyridin-4-yl 248 2 CH₃ CH₃ 2,3-dimethylpyridin-4-yl 249 3CH₃ CH₃ 2,3-dimethylpyridin-4-yl 250 1 CH₂CH₃ CH₂CH₃2,3-dimethylpyridin-4-yl 251 2 CH₂CH₃ CH₂CH₃ 2,3-dimethylpyridin-4-yl252 3 CH₂CH₃ CH₂CH₃ 2,3-dimethylpyridin-4-yl 253 1 CH₃ CH₃3,6-dimethylpyridin-4-yl 254 2 CH₃ CH₃ 3,6-dimethylpyridin-4-yl 255 3CH₃ CH₃ 3,6-dimethylpyridin-4-yl 256 1 CH₂CH₃ CH₂CH₃3,6-dimethylpyridin-4-yl 257 2 CH₂CH₃ CH₂CH₃ 3,63-dimethylpyridin-4-yl258 3 CH₂CH₃ CH₂CH₃ 3,6-dimethylpyridin-4-yl

Exemplary embodiments include compounds having the formula (XIV) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R³ and n are defined herein below inTable 17.

TABLE 17 Entry n R² 1 1 2-CF₃-Phenyl 2 2 2-CF₃-Phenyl 3 3 2-CF₃-Phenyl 41 3-CF₃-Phenyl 5 2 3-CF₃-Phenyl 6 3 3-CF₃-Phenyl 7 1 4-CF₃-Phenyl 8 24-CF₃-Phenyl 9 3 4-CF₃-Phenyl 10 1 2-NH₂-Phenyl 11 2 2-NH₂-Phenyl 12 32-NH₂-Phenyl 13 1 3-NH₂-Phenyl 14 2 3-NH₂-Phenyl 15 3 3-NH₂-Phenyl 16 14-NH₂-Phenyl 17 2 4-NH₂-Phenyl 18 3 4-NH₂-Phenyl 19 1 2-tBu-Phenyl 20 22-tBu-Phenyl 21 3 2-tBu-Phenyl 22 1 3-tBu-Phenyl 23 2 3-tBu-Phenyl 24 33-tBu-Phenyl 25 1 4-tBu-Phenyl 26 2 4-tBu-Phenyl 27 3 4-tBu-Phenyl 28 12-NO₂-Phenyl 29 2 2-NO₂-Phenyl 30 3 2-NO₂-Phenyl 31 1 3-NO₂-Phenyl 32 23-NO₂-Phenyl 33 3 3-NO₂-Phenyl 34 1 4-NO₂-Phenyl 35 2 4-NO₂-Phenyl 36 34-NO₂-Phenyl 37 1 2-SCH₃-Phenyl 38 2 2-SCH₃-Phenyl 39 3 2-SCH₃-Phenyl 401 3-SCH₃-Phenyl 41 2 3-SCH₃-Phenyl 42 3 3-SCH₃-Phenyl 43 1 4-SCH₃-Phenyl44 2 4-SCH₃-Phenyl 45 3 4-SCH₃-Phenyl 46 1 2-SO₂CH₃-Phenyl 47 22-SO₂CH₃-Phenyl 48 3 2-SO₂CH₃-Phenyl 49 1 3-SO₂CH₃-Phenyl 50 23-SO₂CH₃-Phenyl 51 3 3-SO₂CH₃-Phenyl 52 1 4-SO₂CH₃-Phenyl 53 24-SO₂CH₃-Phenyl 54 3 4-SO₂CH₃-Phenyl 55 1 2-SO₂NH₂-Phenyl 56 22-SO₂NH₂-Phenyl 57 3 2-SO₂NH₂-Phenyl 58 1 3-SO₂NH₂-Phenyl 59 23-SO₂NH₂-Phenyl 60 3 3-SO₂NH₂-Phenyl 61 1 4-SO₂NH₂-Phenyl 62 24-SO₂NH₂-Phenyl 63 3 4-SO₂NH₂-Phenyl 64 1 2-CONH₂-Phenyl 65 22-CONH₂-Phenyl 66 3 2-CONH₂-Phenyl 67 1 3-CONH₂-Phenyl 68 23-CONH₂-Phenyl 69 3 3-CONH₂-Phenyl 70 1 4-CONH₂-Phenyl 71 24-CONH₂-Phenyl 72 3 4-CONH₂-Phenyl 73 1 2-Br-Phenyl 74 2 2-Br-Phenyl 753 2-Br-Phenyl 76 1 3-Br-Phenyl 77 2 3-Br-Phenyl 78 3 3-Br-Phenyl 79 12,3-di-CH₃-phenyl 80 2 2,3-di-CH₃-phenyl 81 3 2,3-di-CH₃-phenyl 82 12,4-di-CH₃-phenyl 83 2 2,4-di-CH₃-phenyl 84 3 2,4-di-CH₃-phenyl 85 12,5-di-CH₃-phenyl 86 2 2,5-di-CH₃-phenyl 87 3 2,5-di-CH₃-phenyl 88 12,6-di-CH₃-phenyl 89 2 2,6-di-CH₃-phenyl 90 3 2,6-di-CH₃-phenyl 91 13,4-di-CH₃-phenyl 92 2 3,4-di-CH₃-phenyl 93 3 3,4-di-CH₃-phenyl 94 13,5-di-CH₃-phenyl 95 2 3,5-di-CH₃-phenyl 96 3 3,5-di-CH₃-phenyl 97 12,3-di-Cl-phenyl 98 2 2,3-di-Cl-phenyl 99 3 2,3-di-Cl-phenyl 100 12,4-di-Cl-phenyl 101 2 2,4-di-Cl-phenyl 102 3 2,4-di-Cl-phenyl 103 12,5-di-Cl-phenyl 104 2 2,5-di-Cl-phenyl 105 3 2,5-di-Cl-phenyl 106 12,6-di-Cl-phenyl 107 2 2,6-di-Cl-phenyl 108 3 2,6-di-Cl-phenyl 109 13,4-di-Cl-phenyl 110 2 3,4-di-Cl-phenyl 111 3 3,4-di-Cl-phenyl 112 13,5-di-Cl-phenyl 113 2 3,5-di-Cl-phenyl 114 3 3,5-di-Cl-phenyl 115 12-morpholino-4-CH₃-phenyl 116 2 2-morpholino-4-CH₃-phenyl 117 32-morpholino-4-CH₃-phenyl 118 1 2-morpholino-4-CN-phenyl 119 22-morpholino-4-CN-phenyl 120 3 2-morpholino-4-CN-phenyl 121 12-morpholino-4-OH-phenyl 122 2 2-morpholino-4-OH-phenyl 123 32-morpholino-4-OH-phenyl 124 1 2,3-dimethylpyridin-4-yl 125 22,3-dimethylpyridin-4-yl 126 3 2,3-dimethylpyridin-4-yl 127 13,6-dimethylpyridin-4-yl 128 2 3,6-dimethylpyridin-4-yl 129 33,6-dimethylpyridin-4-yl

Exemplary embodiments include compounds having the formula (XV) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R³ and n are defined herein below inTable 18.

TABLE 18 Entry n R² 1 1 2-CF₃-Phenyl 2 2 2-CF₃-Phenyl 3 3 2-CF₃-Phenyl 41 3-CF₃-Phenyl 5 2 3-CF₃-Phenyl 6 3 3-CF₃-Phenyl 7 1 4-CF₃-Phenyl 8 24-CF₃-Phenyl 9 3 4-CF₃-Phenyl 10 1 2-NH₂-Phenyl 11 2 2-NH₂-Phenyl 12 32-NH₂-Phenyl 13 1 3-NH₂-Phenyl 14 2 3-NH₂-Phenyl 15 3 3-NH₂-Phenyl 16 14-NH₂-Phenyl 17 2 4-NH₂-Phenyl 18 3 4-NH₂-Phenyl 19 1 2-tBu-Phenyl 20 22-tBu-Phenyl 21 3 2-tBu-Phenyl 22 1 3-tBu-Phenyl 23 2 3-tBu-Phenyl 24 33-tBu-Phenyl 25 1 4-tBu-Phenyl 26 2 4-tBu-Phenyl 27 3 4-tBu-Phenyl 28 12-NO₂-Phenyl 29 2 2-NO₂-Phenyl 30 3 2-NO₂-Phenyl 31 1 3-NO₂-Phenyl 32 23-NO₂-Phenyl 33 3 3-NO₂-Phenyl 34 1 4-NO₂-Phenyl 35 2 4-NO₂-Phenyl 36 34-NO₂-Phenyl 37 1 2-SCH₃-Phenyl 38 2 2-SCH₃-Phenyl 39 3 2-SCH₃-Phenyl 401 3-SCH₃-Phenyl 41 2 3-SCH₃-Phenyl 42 3 3-SCH₃-Phenyl 43 1 4-SCH₃-Phenyl44 2 4-SCH₃-Phenyl 45 3 4-SCH₃-Phenyl 46 1 2-SO₂CH₃-Phenyl 47 22-SO₂CH₃-Phenyl 48 3 2-SO₂CH₃-Phenyl 49 1 3-SO₂CH₃-Phenyl 50 23-SO₂CH₃-Phenyl 51 3 3-SO₂CH₃-Phenyl 52 1 4-SO₂CH₃-Phenyl 53 24-SO₂CH₃-Phenyl 54 3 4-SO₂CH₃-Phenyl 55 1 2-SO₂NH₂-Phenyl 56 22-SO₂NH₂-Phenyl 57 3 2-SO₂NH₂-Phenyl 58 1 3-SO₂NH₂-Phenyl 59 23-SO₂NH₂-Phenyl 60 3 3-SO₂NH₂-Phenyl 61 1 4-SO₂NH₂-Phenyl 62 24-SO₂NH₂-Phenyl 63 3 4-SO₂NH₂-Phenyl 64 1 2-CONH₂-Phenyl 65 22-CONH₂-Phenyl 66 3 2-CONH₂-Phenyl 67 1 3-CONH₂-Phenyl 68 23-CONH₂-Phenyl 69 3 3-CONH₂-Phenyl 70 1 4-CONH₂-Phenyl 71 24-CONH₂-Phenyl 72 3 4-CONH₂-Phenyl 73 1 2-Br-Phenyl 74 2 2-Br-Phenyl 753 2-Br-Phenyl 76 1 3-Br-Phenyl 77 2 3-Br-Phenyl 78 3 3-Br-Phenyl 79 12,3-di-CH₃-phenyl 80 2 2,3-di-CH₃-phenyl 81 3 2,3-di-CH₃-phenyl 82 12,4-di-CH₃-phenyl 83 2 2,4-di-CH₃-phenyl 84 3 2,4-di-CH₃-phenyl 85 12,5-di-CH₃-phenyl 86 2 2,5-di-CH₃-phenyl 87 3 2,5-di-CH₃-phenyl 88 12,6-di-CH₃-phenyl 89 2 2,6-di-CH₃-phenyl 90 3 2,6-di-CH₃-phenyl 91 13,4-di-CH₃-phenyl 92 2 3,4-di-CH₃-phenyl 93 3 3,4-di-CH₃-phenyl 94 13,5-di-CH₃-phenyl 95 2 3,5-di-CH₃-phenyl 96 3 3,5-di-CH₃-phenyl 97 12,3-di-Cl-phenyl 98 2 2,3-di-Cl-phenyl 99 3 2,3-di-Cl-phenyl 100 12,4-di-Cl-phenyl 101 2 2,4-di-Cl-phenyl 102 3 2,4-di-Cl-phenyl 103 12,5-di-Cl-phenyl 104 2 2,5-di-Cl-phenyl 105 3 2,5-di-Cl-phenyl 106 12,6-di-Cl-phenyl 107 2 2,6-di-Cl-phenyl 108 3 2,6-di-Cl-phenyl 109 13,4-di-Cl-phenyl 110 2 3,4-di-Cl-phenyl 111 3 3,4-di-Cl-phenyl 112 13,5-di-Cl-phenyl 113 2 3,5-di-Cl-phenyl 114 3 3,5-di-Cl-phenyl 115 12-morpholino-4-CH₃-phenyl 116 2 2-morpholino-4-CH₃-phenyl 117 32-morpholino-4-CH₃-phenyl 118 1 2-morpholino-4-CN-phenyl 119 22-morpholino-4-CN-phenyl 120 3 2-morpholino-4-CN-phenyl 121 12-morpholino-4-OH-phenyl 122 2 2-morpholino-4-OH-phenyl 123 32-morpholino-4-OH-phenyl 124 1 2,3-dimethylpyridin-4-yl 125 22,3-dimethylpyridin-4-yl 126 3 2,3-dimethylpyridin-4-yl 127 13,6-dimethylpyridin-4-yl 128 2 3,6-dimethylpyridin-4-yl 129 33,6-dimethylpyridin-4-yl

Exemplary embodiments include compounds having the formula (XVI) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R³ and n are defined herein below inTable 19.

TABLE 19 Entry n R² 1 1 2-CF₃-Phenyl 2 2 2-CF₃-Phenyl 3 3 2-CF₃-Phenyl 41 3-CF₃-Phenyl 5 2 3-CF₃-Phenyl 6 3 3-CF₃-Phenyl 7 1 4-CF₃-Phenyl 8 24-CF₃-Phenyl 9 3 4-CF₃-Phenyl 10 1 2-NH₂-Phenyl 11 2 2-NH₂-Phenyl 12 32-NH₂-Phenyl 13 1 3-NH₂-Phenyl 14 2 3-NH₂-Phenyl 15 3 3-NH₂-Phenyl 16 14-NH₂-Phenyl 17 2 4-NH₂-Phenyl 18 3 4-NH₂-Phenyl 19 1 2-tBu-Phenyl 20 22-tBu-Phenyl 21 3 2-tBu-Phenyl 22 1 3-tBu-Phenyl 23 2 3-tBu-Phenyl 24 33-tBu-Phenyl 25 1 4-tBu-Phenyl 26 2 4-tBu-Phenyl 27 3 4-tBu-Phenyl 28 12-NO₂-Phenyl 29 2 2-NO₂-Phenyl 30 3 2-NO₂-Phenyl 31 1 3-NO₂-Phenyl 32 23-NO₂-Phenyl 33 3 3-NO₂-Phenyl 34 1 4-NO₂-Phenyl 35 2 4-NO₂-Phenyl 36 34-NO₂-Phenyl 37 1 2-SCH₃-Phenyl 38 2 2-SCH₃-Phenyl 39 3 2-SCH₃-Phenyl 401 3-SCH₃-Phenyl 41 2 3-SCH₃-Phenyl 42 3 3-SCH₃-Phenyl 43 1 4-SCH₃-Phenyl44 2 4-SCH₃-Phenyl 45 3 4-SCH₃-Phenyl 46 1 2-SO₂CH₃-Phenyl 47 22-SO₂CH₃-Phenyl 48 3 2-SO₂CH₃-Phenyl 49 1 3-SO₂CH₃-Phenyl 50 23-SO₂CH₃-Phenyl 51 3 3-SO₂CH₃-Phenyl 52 1 4-SO₂CH₃-Phenyl 53 24-SO₂CH₃-Phenyl 54 3 4-SO₂CH₃-Phenyl 55 1 2-SO₂NH₂-Phenyl 56 22-SO₂NH₂-Phenyl 57 3 2-SO₂NH₂-Phenyl 58 1 3-SO₂NH₂-Phenyl 59 23-SO₂NH₂-Phenyl 60 3 3-SO₂NH₂-Phenyl 61 1 4-SO₂NH₂-Phenyl 62 24-SO₂NH₂-Phenyl 63 3 4-SO₂NH₂-Phenyl 64 1 2-CONH₂-Phenyl 65 22-CONH₂-Phenyl 66 3 2-CONH₂-Phenyl 67 1 3-CONH₂-Phenyl 68 23-CONH₂-Phenyl 69 3 3-CONH₂-Phenyl 70 1 4-CONH₂-Phenyl 71 24-CONH₂-Phenyl 72 3 4-CONH₂-Phenyl 73 1 2-Br-Phenyl 74 2 2-Br-Phenyl 753 2-Br-Phenyl 76 1 3-Br-Phenyl 77 2 3-Br-Phenyl 78 3 3-Br-Phenyl 79 12,3-di-CH₃-phenyl 80 2 2,3-di-CH₃-phenyl 81 3 2,3-di-CH₃-phenyl 82 12,4-di-CH₃-phenyl 83 2 2,4-di-CH₃-phenyl 84 3 2,4-di-CH₃-phenyl 85 12,5-di-CH₃-phenyl 86 2 2,5-di-CH₃-phenyl 87 3 2,5-di-CH₃-phenyl 88 12,6-di-CH₃-phenyl 89 2 2,6-di-CH₃-phenyl 90 3 2,6-di-CH₃-phenyl 91 13,4-di-CH₃-phenyl 92 2 3,4-di-CH₃-phenyl 93 3 3,4-di-CH₃-phenyl 94 13,5-di-CH₃-phenyl 95 2 3,5-di-CH₃-phenyl 96 3 3,5-di-CH₃-phenyl 97 12,3-di-Cl-phenyl 98 2 2,3-di-Cl-phenyl 99 3 2,3-di-Cl-phenyl 100 12,4-di-Cl-phenyl 101 2 2,4-di-Cl-phenyl 102 3 2,4-di-Cl-phenyl 103 12,5-di-Cl-phenyl 104 2 2,5-di-Cl-phenyl 105 3 2,5-di-Cl-phenyl 106 12,6-di-Cl-phenyl 107 2 2,6-di-Cl-phenyl 108 3 2,6-di-Cl-phenyl 109 13,4-di-Cl-phenyl 110 2 3,4-di-Cl-phenyl 111 3 3,4-di-Cl-phenyl 112 13,5-di-Cl-phenyl 113 2 3,5-di-Cl-phenyl 114 3 3,5-di-Cl-phenyl 115 12-morpholino-4-CH₃-phenyl 116 2 2-morpholino-4-CH₃-phenyl 117 32-morpholino-4-CH₃-phenyl 118 1 2-morpholino-4-CN-phenyl 119 22-morpholino-4-CN-phenyl 120 3 2-morpholino-4-CN-phenyl 121 12-morpholino-4-OH-phenyl 122 2 2-morpholino-4-OH-phenyl 123 32-morpholino-4-OH-phenyl 124 1 2,3-dimethylpyridin-4-yl 125 22,3-dimethylpyridin-4-yl 126 3 2,3-dimethylpyridin-4-yl 127 13,6-dimethylpyridin-4-yl 128 2 3,6-dimethylpyridin-4-yl 129 33,6-dimethylpyridin-4-yl

Exemplary embodiments include compounds having the formula (XVII) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R³ and n are defined herein below inTable 20.

TABLE 20 Entry n R² 1 1 2-CF₃-Phenyl 2 2 2-CF₃-Phenyl 3 3 2-CF₃-Phenyl 41 3-CF₃-Phenyl 5 2 3-CF₃-Phenyl 6 3 3-CF₃-Phenyl 7 1 4-CF₃-Phenyl 8 24-CF₃-Phenyl 9 3 4-CF₃-Phenyl 10 1 2-NH₂-Phenyl 11 2 2-NH₂-Phenyl 12 32-NH₂-Phenyl 13 1 3-NH₂-Phenyl 14 2 3-NH₂-Phenyl 15 3 3-NH₂-Phenyl 16 14-NH₂-Phenyl 17 2 4-NH₂-Phenyl 18 3 4-NH₂-Phenyl 19 1 2-tBu-Phenyl 20 22-tBu-Phenyl 21 3 2-tBu-Phenyl 22 1 3-tBu-Phenyl 23 2 3-tBu-Phenyl 24 33-tBu-Phenyl 25 1 4-tBu-Phenyl 26 2 4-tBu-Phenyl 27 3 4-tBu-Phenyl 28 12-NO₂-Phenyl 29 2 2-NO₂-Phenyl 30 3 2-NO₂-Phenyl 31 1 3-NO₂-Phenyl 32 23-NO₂-Phenyl 33 3 3-NO₂-Phenyl 34 1 4-NO₂-Phenyl 35 2 4-NO₂-Phenyl 36 34-NO₂-Phenyl 37 1 2-SCH₃-Phenyl 38 2 2-SCH₃-Phenyl 39 3 2-SCH₃-Phenyl 401 3-SCH₃-Phenyl 41 2 3-SCH₃-Phenyl 42 3 3-SCH₃-Phenyl 43 1 4-SCH₃-Phenyl44 2 4-SCH₃-Phenyl 45 3 4-SCH₃-Phenyl 46 1 2-SO₂CH₃-Phenyl 47 22-SO₂CH₃-Phenyl 48 3 2-SO₂CH₃-Phenyl 49 1 3-SO₂CH₃-Phenyl 50 23-SO₂CH₃-Phenyl 51 3 3-SO₂CH₃-Phenyl 52 1 4-SO₂CH3-Phenyl 53 24-SO₂CH₃-Phenyl 54 3 4-SO₂CH₃-Phenyl 55 1 2-SO₂NH₂-Phenyl 56 22-SO₂NH₂-Phenyl 57 3 2-SO₂NH₂-Phenyl 58 1 3-SO₂NH₂-Phenyl 59 23-SO₂NH₂-Phenyl 60 3 3-SO₂NH₂-Phenyl 61 1 4-SO₂NH₂-Phenyl 62 24-SO₂NH₂-Phenyl 63 3 4-SO₂NH₂-Phenyl 64 1 2-CONH₂-Phenyl 65 22-CONH₂-Phenyl 66 3 2-CONH₂-Phenyl 67 1 3-CONH₂-Phenyl 68 23-CONH₂-Phenyl 69 3 3-CONH₂-Phenyl 70 1 4-CONH₂-Phenyl 71 24-CONH₂-Phenyl 72 3 4-CONH₂-Phenyl 73 1 2-Br-Phenyl 74 2 2-Br-Phenyl 753 2-Br-Phenyl 76 1 3-Br-Phenyl 77 2 3-Br-Phenyl 78 3 3-Br-Phenyl 79 12,3-di-CH₃-phenyl 80 2 2,3-di-CH₃-phenyl 81 3 2,3-di-CH₃-phenyl 82 12,4-di-CH₃-phenyl 83 2 2,4-di-CH₃-phenyl 84 3 2,4-di-CH₃-phenyl 85 12,5-di-CH₃-phenyl 86 2 2,5-di-CH₃-phenyl 87 3 2,5-di-CH₃-phenyl 88 12,6-di-CH₃-phenyl 89 2 2,6-di-CH₃-phenyl 90 3 2,6-di-CH₃-phenyl 91 13,4-di-CH₃-phenyl 92 2 3,4-di-CH₃-phenyl 93 3 3,4-di-CH₃-phenyl 94 13,5-di-CH₃-phenyl 95 2 3,5-di-CH₃-phenyl 96 3 3,5-di-CH₃-phenyl 97 12,3-di-Cl-phenyl 98 2 2,3-di-Cl-phenyl 99 3 2,3-di-Cl-phenyl 100 12,4-di-Cl-phenyl 101 2 2,4-di-Cl-phenyl 102 3 2,4-di-Cl-phenyl 103 12,5-di-Cl-phenyl 104 2 2,5-di-Cl-phenyl 105 3 2,5-di-Cl-phenyl 106 12,6-di-Cl-phenyl 107 2 2,6-di-Cl-phenyl 108 3 2,6-di-Cl-phenyl 109 13,4-di-Cl-phenyl 110 2 3,4-di-Cl-phenyl 111 3 3,4-di-Cl-phenyl 112 13,5-di-Cl-phenyl 113 2 3,5-di-Cl-phenyl 114 3 3,5-di-Cl-phenyl 115 12-morpholino-4-CH₃-phenyl 116 2 2-morpholino-4-CH₃-phenyl 117 32-morpholino-4-CH₃-phenyl 118 1 2-morpholino-4-CN-phenyl 119 22-morpholino-4-CN-phenyl 120 3 2-morpholino-4-CN-phenyl 121 12-morpholino-4-OH-phenyl 122 2 2-morpholino-4-OH-phenyl 123 32-morpholino-4-OH-phenyl 124 1 2,3-dimethylpyridin-4-yl 125 22,3-dimethylpyridin-4-yl 126 3 2,3-dimethylpyridin-4-yl 127 13,6-dimethylpyridin-4-yl 128 2 3,6-dimethylpyridin-4-yl 129 33,6-dimethylpyridin-4-yl

For the purposes of demonstrating the manner in which the compounds ofthe present invention are named and referred to herein, the compoundhaving the formula:

has the chemical name3-(2-(5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one.

For the purposes of demonstrating the manner in which the compounds ofthe present invention are named and referred to herein, the compoundhaving the formula:

has the chemical name3-(2-(6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one.

For the purposes of the present invention, a compound depicted by theracemic formula, for example:

will stand equally well for either of the two enantiomers having theformula:

or the formula:

or mixtures thereof, or in the case where a second chiral center ispresent, all diastereomers.

In all of the embodiments provided herein, examples of suitable optionalsubstituents are not intended to limit the scope of the claimedinvention. The compounds of the invention may contain any of thesubstituents, or combinations of substituents, provided herein.

Process

The present invention further relates to a process for preparing thesigma-2 receptor binders and sigma-2 receptor activity modulators of thepresent invention.

Compounds of the present teachings can be prepared in accordance withthe procedures outlined herein, from commercially available startingmaterials, compounds known in the literature, or readily preparedintermediates, by employing standard synthetic methods and proceduresknown to those skilled in the art. Standard synthetic methods andprocedures for the preparation of organic molecules and functional grouptransformations and manipulations can be readily obtained from therelevant scientific literature or from standard textbooks in the field.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions can vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures. Those skilled in the art of organic synthesiswill recognize that the nature and order of the synthetic stepspresented can be varied for the purpose of optimizing the formation ofthe compounds described herein.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry(e.g., UV-visible), mass spectrometry, or by chromatography such as highpressure liquid chromatography (HPLC), gas chromatography (GC),gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

Preparation of the compounds can involve protection and deprotection ofvarious chemical groups. The need for protection and deprotection andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene et al., Protective Groups in OrganicSynthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of whichis incorporated by reference herein for all purposes.

The reactions or the processes described herein can be carried out insuitable solvents which can be readily selected by one skilled in theart of organic synthesis. Suitable solvents typically are substantiallynonreactive with the reactants, intermediates, and/or products at thetemperatures at which the reactions are carried out, i.e., temperaturesthat can range from the solvent's freezing temperature to the solvent'sboiling temperature. A given reaction can be carried out in one solventor a mixture of more than one solvent. Depending on the particularreaction step, suitable solvents for a particular reaction step can beselected.

The compounds of these teachings can be prepared by methods known in theart of organic chemistry. The reagents used in the preparation of thecompounds of these teachings can be either commercially obtained or canbe prepared by standard procedures described in the literature. Forexample, compounds of the present invention can be prepared according tothe method illustrated in the General Synthetic Schemes:

General Synthetic Schemes for Preparation of Compounds

The reagents used in the preparation of the compounds of this inventioncan be either commercially obtained or can be prepared by standardprocedures described in the literature. In accordance with thisinvention, compounds in the genus may be produced by one of thefollowing reaction schemes.

Compounds of the disclosure may be prepared according to any of theprocess outlined in Schemes 1-8.

Accordingly, a suitably substituted compound (1) a known compound orcompound prepared by known methods, is reacted with a compound of theformula (2), a known compound or a compound prepared by known methods,in the presence of a palladium catalyst such as palladium acetate,palladium bis(triphenylphosphine) dichloride, palladiumtetrakis(triphenylphospine), bis(acetonitrile) dichloropalladium[1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium,Tris(dibenzylideneacetone)dipalladium(0), and the like, in the presenceof a base such as potassium t-butoxide, sodium t-butoxide, lithiumt-butoxide, potassium carbonate, sodium carbonate, lithium carbonate,cesium carbonate, sodium hydroxide, lithium hydroxide, potassiumhydroxide, and the like, optionally in the presence of an organic basesuch as triethylamine, diisopropylethyl amine, pyridine, and the like,optionally in the presence of a bis(diphenylphosphino) derived compoundsuch as 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene,2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,1,1′-binaphthalene-2,2′-diyl)bis[bis(3,5-dimethylphenyl)phosphine],5,5′-bis[di(3,5-xylyl) phosphino]-4,4′-bi-1,3-benzodioxole,5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole, and the like, in a solvent such astoluene, benzene, xylene, 1,4-dioxane, tetrahydrofuran, methylenechloride, 1,2-dichloroethane, N,N-dimethylformamide,N,N-dimethylacetamide, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (3). Acompound of the formula (3) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like,optionally in the presence of an organic solvent such as methylenechloride, dichloroethane, 1,4-dioxane, tetrahydrofuran, methanol,ethanol, and the like, to provide a compound of the formula (4).

A suitably substituted compound (5) a known compound or compoundprepared by known methods, is reacted with a compound of the formula(6), a known compound or a compound prepared by known methods, in thepresence of a palladium catalyst such as palladium acetate, palladiumbis(triphenylphosphine) dichloride, palladiumtetrakis(triphenylphospine), bis(acetonitrile) dichloropalladium[1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium,Tris(dibenzylideneacetone)dipalladium(0), and the like, in the presenceof a base such as potassium t-butoxide, sodium t-butoxide, lithiumt-butoxide, potassium carbonate, sodium carbonate, lithium carbonate,cesium carbonate, sodium hydroxide, lithium hydroxide, potassiumhydroxide, and the like, optionally in the presence of an organic basesuch as triethylamine, diisopropylethyl amine, pyridine, and the like,optionally in the presence of a bis(diphenylphosphino) derived compoundsuch as 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene,2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,1,1′-binaphthalene-2,2′-diyl)bis[bis(3,5-dimethylphenyl)phosphine],5,5′-bis[di(3,5-xylyl) phosphino]-4,4′-bi-1,3-benzodioxole,5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole,and the like, in a solvent such as toluene, benzene, xylene,1,4-dioxane, tetrahydrofuran, methylene chloride, 1,2-dichloroethane,N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionallywith heating, optionally with microwave irradiation to provide acompound of the formula (7). A compound of the formula (7) is reactedwith an acid such as trifluoroacetic acid, hydrochloric acid, sulfuricacid, and the like, optionally in the presence of an organic solventsuch as methylene chloride, dichloroethane, 1,4-dioxane,tetrahydrofuran, methanol, ethanol, and the like, to provide a compoundof the formula (8).

A suitably substituted compound (9) a known compound or compoundprepared by known methods, is reacted with a compound of the formula(10), a known compound or a compound prepared by known methods, in thepresence of a palladium catalyst such as palladium acetate, palladiumbis(triphenylphosphine) dichloride, palladiumtetrakis(triphenylphospine), bis(acetonitrile) dichloropalladium[1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium,Tris(dibenzylideneacetone)dipalladium(0), and the like, in the presenceof a base such as potassium t-butoxide, sodium t-butoxide, lithiumt-butoxide, potassium carbonate, sodium carbonate, lithium carbonate,cesium carbonate, sodium hydroxide, lithium hydroxide, potassiumhydroxide, and the like, optionally in the presence of an organic basesuch as triethylamine, diisopropylethyl amine, pyridine, and the like,optionally in the presence of a bis(diphenylphosphino) derived compoundsuch as 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene,2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,1,1′-binaphthalene-2,2′-diyl)bis[bis(3,5-dimethylphenyl)phosphine],5,5′-bis[di(3,5-xylyl) phosphino]-4,4′-bi-1,3-benzodioxole,5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole,and the like, in a solvent such as toluene, benzene, xylene,1,4-dioxane, tetrahydrofuran, methylene chloride, 1,2-dichloroethane,N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionallywith heating, optionally with microwave irradiation to provide acompound of the formula (11). A compound of the formula (11) is reactedwith hydrogen in the presence of a palladium catalyst such as palladiumon carbon, palladium on celite, palladium on barium sulfate, palladiumacetate, palladium bis(triphenylphosphine) dichloride, palladiumtetrakis(triphenylphospine), and the like, in a solvent such asmethanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran,1,4-dioxane, and the like to provide a compound of the formula (12).

A suitably substituted compound (13) a known compound or compoundprepared by known methods, is reacted with a compound of the formula(14), a known compound or a compound prepared by known methods, in thepresence of a palladium catalyst such as palladium acetate, palladiumbis(triphenylphosphine) dichloride, palladiumtetrakis(triphenylphospine), bis(acetonitrile) dichloropalladium[1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium,Tris(dibenzylideneacetone)dipalladium(0), and the like, in the presenceof a base such as potassium t-butoxide, sodium t-butoxide, lithiumt-butoxide, potassium carbonate, sodium carbonate, lithium carbonate,cesium carbonate, sodium hydroxide, lithium hydroxide, potassiumhydroxide, and the like, optionally in the presence of an organic basesuch as triethylamine, diisopropylethyl amine, pyridine, and the like,optionally in the presence of a bis(diphenylphosphino) derived compoundsuch as 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene,2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,1,1′-binaphthalene-2,2′-diyl)bis[bis(3,5-dimethylphenyl)phosphine],5,5′-bis[di(3,5-xylyl) phosphino]-4,4′-bi-1,3-benzodioxole,5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole,and the like, in a solvent such as toluene, benzene, xylene,1,4-dioxane, tetrahydrofuran, methylene chloride, 1,2-dichloroethane,N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionallywith heating, optionally with microwave irradiation to provide acompound of the formula (15). A compound of the formula (15) is reactedwith hydrogen in the presence of a palladium catalyst such as palladiumon carbon, palladium on celite, palladium on barium sulfate, palladiumacetate, palladium bis(triphenylphosphine) dichloride, palladiumtetrakis(triphenylphospine), and the like, in a solvent such asmethanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran,1,4-dioxane, and the like to provide a compound of the formula (16).

A suitably substituted compound of formula (17), a known compound orcompound prepared by known methods, is reacted with a compound of theformula (18), wherein X is a leaving group such as chlorine, bromine,iodine, mesylate, tosylate, and the like, in the presence of a base suchas lithium diisopropylamide, sodium diisopropylamide, potassiumdiisopropylamide, lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodiumhydride, and the like in an organic solvent such as tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide,and the like, to provide a compound of the formula (19). A compound ofthe formula (19) is then treated with paraformaldehyde in the presenceof an acid such as sulfuric acid, hydrochloric acid, and the like, in anthe presence of acetic acid, and optionally in an organic solvent suchas methanol, ethanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,dimethylformamide, dimethylacetamide, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (20). A compound of the formula (20) is then treated with abase such as sodium hydroxide, potassium hydroxide, lithium hydroxide,and the like, in an solvent such as water, methanol, ethanol,isopropanol, and the like, optionally with heating, and then treatedwith an acid such as sulfuric acid, hydrochloric acid, and the like, ina solvent such as water, methanol, ethanol, isopropanol, and the like,to provide a compound of the formula (21). A compound of the formula(21) is then converted to a compound of the formula (22), wherein LG isa leaving group such as mesylate, tosylate, nosylate, bromide, and thelike, using methods that are known to one skilled in the art. Thus, acompound of the formula (21) is treated with a sulfonyl chloride such asmethanesulfonyl chloride, toluenesulfonyl chloride p-nitrophenylsulfonyl chloride, and the like, in the presence of a base such astriethylamine, diisopropyl amine, pyridine, 2,6-lutidine, and the like,in an organic solvent such as methylene chloride, dichloroethane,tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, tetrahydrofuran,1,4-dioxane and the like to provide a compound of the formula (22).Alternatively, a compound of the formula (21) is reacted with carbontetrabromide in the presence of triphenylphosphine in a solvent such asmethylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like,optionally with heating, optionally with microwave irradiation, toprovide a compound of the formula (22). A compound of the formula (22)is reacted with a compound of the formula (23), a known compound orcompound prepared by known methods, in an organic solvent such astetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide,dimethylacetamide, and the like, optionally in the presence of a basesuch as triethylamine, diisopropylethylamine, pyridine, 2,6 lutidine,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (24).

A suitably substituted compound of formula (25), a known compound orcompound prepared by known methods, is reacted with a compound of theformula (26), wherein X is a leaving group such as chlorine, bromine,iodine, mesylate, tosylate, and the like, in the presence of a base suchas lithium diisopropylamide, sodium diisopropylamide, potassiumdiisopropylamide, lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodiumhydride, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, and thelike in an organic solvent such as tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, and the like,to provide a compound of the formula (27). A compound of the formula(27) is then treated with paraformaldehyde in the presence of an acidsuch as sulfuric acid, hydrochloric acid, and the like, in the presenceof acetic acid, and optionally in an organic solvent such as methanol,ethanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,dimethylformamide, dimethylacetamide, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (28). A compound of the formula (28) is then treated with abase such as sodium hydroxide, potassium hydroxide, lithium hydroxide,and the like, in an solvent such as water, methanol, ethanol,isopropanol, and the like, optionally with heating, and then treatedwith an acid such as sulfuric acid, hydrochloric acid, and the like, ina solvent such as water, methanol, ethanol, isopropanol, and the like,optionally with heating, to provide a compound of the formula (29). Acompound of the formula (29) is then converted to a compound of theformula (30), wherein LG is a leaving group such as mesylate, tosylate,nosylate, bromide, and the like, using methods that are known to oneskilled in the art. Thus, a compound of the formula (29) is treated witha sulfonyl chloride such as methanesulfonyl chloride, toluenesulfonylchloride p-nitrophenyl sulfonyl chloride, and the like, in the presenceof a base such as triethylamine, diisopropyl amine, pyridine,2,6-lutidine, and the like, in an organic solvent such as methylenechloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like toprovide a compound of the formula (30). Alternatively, a compound of theformula (29) is reacted with carbon tetrabromide in the presence oftriphenylphosphine in a solvent such as methylene chloride,dichloroethane, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide,tetrahydrofuran, 1,4-dioxane and the like, optionally with heating,optionally with microwave irradiation, to provide a compound of theformula (30). A compound of the formula (30) is reacted with a compoundof the formula (31), a known compound or compound prepared by knownmethods, in an organic solvent such as tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, pyridine, 2,6 lutidine, and the like, optionallywith heating, optionally with microwave irradiation to provide acompound of the formula (32).

Compounds of formula (37) may be prepared according to the processoutlined in Scheme 7.

A compound of the formula (33) is reacted with a base such as sodiumhydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate,potassium carbonate, lithium carbonate and the like, in the presence ofa solvent such as methanol, ethanol, isopropanol, water, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (34). A compound of the formula (34)is then reacted with iodine in the presence of a base such as sodiumbicarbonate, potassium bicarbonate, lithium bicarbonate, sodiumcarbonate, potassium carbonate, lithium bicarbonate, sodium hydroxide,potassium hydroxide, lithium hydroxide, and the like, in the presence ofa solvent such as tetrahydrofuran, ethyl ether, 1,4-dioxane, and thelike to provide a compound of the formula (35). A compound of theformula (35) is reacted with a compound of the formula (36), a knowncompound or compound prepared by known methods, in an organic solventsuch as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,dimethylformamide, dimethylacetamide, and the like, optionally in thepresence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6 lutidine, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (37).

Compounds of formula (46) may be prepared according to the processoutlined in Scheme 8.

A compound of the formula (38) is reacted with ruthenium chloride in thepresence of sodium periodate in a solvent such as acetonitrile,methanol, ethanol, isopropanol, and the like, to provide a compound ofthe formula (39). A compound of the formula (39) is reacted with acompound of the formula (40), a known compound or compound prepared byknown methods, wherein x is a halogen, in the presence of a solvent suchas ethyl ether, tetrahydrofuran, 1,4-dioxane and the like to provide acompound of the formula (41). A compound of the formula (41) is reactedwith ruthenium chloride in the presence of sodium periodate in a solventsuch as acetonitrile, methanol, ethanol, isopropanol, and the like, toprovide a compound of the formula (42). A compound of the formula (42)is reacted with a reducing agent such as lithium borohydride, sodiumborohydride, sodium cyanoborohydride and the like, in a solvent such asmethanol, ethanol, isopropanol, acetonitrile, and the like to provide acompound of the formula (42). A compound of the formula (43) is thenconverted to a compound of the formula (44), wherein LG is a leavinggroup such as mesylate, tosylate, nosylate, bromide, and the like, usingmethods that are known to one skilled in the art. Thus, a compound ofthe formula (43) is treated with a sulfonyl chloride such asmethanesulfonyl chloride, toluenesulfonyl chloride p-nitrophenylsulfonyl chloride, and the like, in the presence of a base such astriethylamine, diisopropyl amine, pyridine, 2,6-lutidine, and the like,in an organic solvent such as methylene chloride, dichloroethane,tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, tetrahydrofuran,1,4-dioxane and the like to provide a compound of the formula (44).Alternatively, a compound of the formula (43) is reacted with carbontetrabromide in the presence of triphenylphosphine in a solvent such asmethylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like,optionally with heating, optionally with microwave irradiation, toprovide a compound of the formula (44). A compound of the formula (44)is reacted with a compound of the formula (45), a known compound orcompound prepared by known methods, in an organic solvent such astetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide,dimethylacetamide, and the like, optionally in the presence of a basesuch as triethylamine, diisopropylethylamine, pyridine, 2,6 lutidine,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (46).

The Examples provided below provide representative methods for preparingexemplary compounds of the present invention. The skilled practitionerwill know how to substitute the appropriate reagents, starting materialsand purification methods known to those skilled in the art, in order toprepare the compounds of the present invention.

EXAMPLES

The practice of the invention is illustrated by the followingnon-limiting examples. The Examples provided below providerepresentative methods for preparing exemplary compounds of the presentinvention. The skilled practitioner will know how to substitute theappropriate reagents, starting materials and purification methods knownto those skilled in the art, in order to prepare the compounds of thepresent invention.

In the examples that follow, ¹H-NMR spectra were obtained on a VarianMercury 300-MHz NMR. Purity (%) and mass spectral data were determinedwith a Waters Alliance 2695 HPLC/MS (Waters Symmetry C18, 4.6×75 mm, 3.5m) with a 2996 diode array detector from 210-400 nm.

Example 1: Preparation of methyl 2,2-dimethylpent-4-enoate: Thisreaction was performed in oven-dried glassware under a nitrogenatmosphere. To a well-stirred solution of freshly prepared lithiumdiisopropylamide (1M, 1.10 equiv) in dry 35 ml tetrahydrofuran,isobutyric acid methyl ester (3.32 g, 32.6 mmol, 1.0 equiv) was addeddropwise during 0.5 hours at −78° C. The mixture was allowed to stir atthis temperature for 30 min followed by the addition of allyl bromide(5.35 g, 44.0 mmol) and Hexamethylphosphoramide (HMPA) (2.91 g, 16.3mmol) dropwise over 0.5 h. The reaction mixture was stirred overnight atroom temperature, quenched with 10% HCl (while cooling in ice bath)until acidic (pH=2). The organic layer was separated and the aqueouslayer was extracted with hexanes (3×100 mL). The extract was washed with10% NaHCO₃ (200 mL) and brine (200 mL). The solution was then dried overMgSO₄, concentrated in vacuo and distilled to give pure product. ¹H NMR(400 MHz, CDCl₃) δ 5.73 (dd, J=9.4, 17.7, 1H), 5.04 (dd, J=1.9, 13.5,2H), 4.12 (q, J=7.1, 2H), 2.28 (d, J=7.4, 2H), 1.25 (t, J=7.1, 3H), 1.17(s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 177.42, 134.42, 117.88, 77.68,77.36, 77.04, 60.35, 44.91, 42.25, 24.92, 14.35

The following compounds can be prepared by the procedure of methyl2,2-dimethylpent-4-enoate. The skilled practitioner will know how tosubstitute the appropriate reagents, starting materials and purificationmethods known to those skilled in the art, in order to prepare thecompounds provided herein.

Example 2: Preparation of Ethyl 2,2-diethylpent-4-enoate: The titlecompound was prepared according to the procedure for methyl2,2-dimethylpent-4-enoate, except 2-ethyl-butyric acid ethyl ester wassubstituted for isobutyric acid methyl ester ¹H NMR (300 MHz, CDCl₃) δ5.68 (dd, J=9.9, 17.2, 1H), 5.16-4.97 (m, 2H), 4.14 (q, J=7.1, 2H), 2.33(d, J=7.4, 2H), 1.59 (dt, J=6.5, 7.5, 5H), 1.26 (t, J=7.1, 3H), 0.80 (t,J=7.5, 6H)

Example 3: Preparation of 1-allylcyclobutanecarboxylic acid: Thisreaction was performed in oven-dried glassware under a nitrogenatmosphere. To a well-stirred solution of freshly prepared lithiumdiisopropylamide (1M, 10.76 mmol, 2.30 equiv) in dry 107 mltetrahydrofuran, cyclobutanecarboxylic acid (4.68 g, 46.8 mmol, 1.0equiv) was added dropwise during 0.5 hours at 0° C. The mixture washeated to 50° C. for 6 hours, then cooled to 0° C. followed by theaddition of NaI (0.697 g, 4.68 mmol, 0.1 equiv) in one portion and amixture of allyl bromide (7.58 g, 63.2 mmol, 1.35 equiv) and HMPA (4.18g, 23.4 mmol, 0.5 equiv) dropwise over 0.5 hr. The reaction mixture wasstirred overnight at room temperature, quenched with 10% HCl (whilecooling in ice bath) until acidic (pH=2). The organic layer wasseparated and the aqueous layer was extracted with ether (3×250 mL). Theorganic phases were combined and washed with brine. The solution wasthen dried over MgSO₄ and concentrated in vacuo to afford a crude oilwhich was purified through flash chromatography (silica; ethylacetate/hexanes, 1%˜10%). ¹H NMR (400 MHz, CDCl₃) δ 5.77 (ddt, J=7.1,10.2, 17.2, 1H), 5.17-4.99 (m, 2H), 2.59-2.38 (m, 4H), 2.07-1.84 (m,4H). ¹³C NMR (101 MHz, CDCl₃) δ 184.04, 133.90, 118.19, 47.20, 41.74,29.57, 15.65; Rf, 0.43 (Hexane:Ethyl Acetate 10:1); HRMS (CI): [M+H],calcd for C₃H₁₃O₂, 141.0916; found 141.0911.

The following compounds can be prepared by the procedure of1-allylcyclobutanecarboxylic acid. The skilled practitioner will knowhow to substitute the appropriate reagents, starting materials andpurification methods known to those skilled in the art, in order toprepare the compounds provided herein.

Example 4: Preparation of 1-allylcyclopentanecarboxylic acid: The titlecompound was prepared according to the procedure for1-allylcyclobutanecarboxylic acid, except cyclopentane carboxylic acidwas substituted for cyclobutanecarboxylic acid: ¹H NMR (400 MHz, CDCl₃)δ 5.77 (ddt, J=7.2, 10.2, 17.4, 1H), 5.17-4.94 (m, 2H), 2.38 (d, J=7.2,2H), 2.20-2.02 (m, 2H), 1.79-1.47 (m, 6H). ¹³C NMR (101 MHz, CDCl₃) δ184.94, 134.96, 118.02, 53.75, 42.96, 35.89, 25.47. Rf, 0.50(Hexane:Ethyl Acetate 10:1); HRMS (CI): [M+H], calcd for C₉H₁₅O₂,155.1072; found 155.1068.

Example 5: Preparation of 1-allylcyclohexanecarboxylic acid: The titlecompound was prepared according to the procedure for1-allylcyclobutanecarboxylic acid, except cyclohexane carboxylic acidwas substituted for cyclobutanecarboxylic acid: ¹H NMR (400 MHz, CDCl₃)δ 12.13 (broad, 1H), 5.83-5.63 (m, 1H), 5.12-5.00 (m, 2H), 2.27 (m, 2H),2.04 (m, 2H), 1.66-1.50 (m, 3H), 1.49-1.33 (m, 2H), 1.33-1.17 (m, 3H).

Example 6: Preparation of5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: A mixture ofglacial acetic acid (28.6 g, 477 mmol, 53.6 equiv), paraformaldehyde(0.80 g, 26.7 mmol, 3.0 equiv) and H₂SO₄ (0.5 g, 4.45 mmol, 0.57 equiv)was stirred for 30 min at 70° C. before methyl 2,2-dimethylpent-4-enoate(1.26 g, 8.9 mmol, 1.0 equiv) was added dropwise during 10 min. Thereaction mixture was then maintained at 70˜80° C. and allowed to stirovernight. Acetic acid was removed under reduced pressure and thereaction was quenched with 10% NaHCO₃ solution. The mixture was thenextracted with ethyl acetate (3×50 mL) and the combined organic phasewas concentrated in vacuo to give a crude oil. The crude oil was usedfor next step without further purification.

A mixture of the crude oil (200 mg, 1.0 mmol, 1 equiv) and 30% NaOH (800mg NaOH, 20 mmol, 20 equiv) aqueous solution was refluxed for 2 hours.The mixture was cooled in an ice bath and excess 30% H₂SO₄ was addeduntil acidic (pH<2). The resulting mixture was extracted with ethylacetate (3×25 mL), the combined organic phase was washed with 10%NaHCO₃, (50 mL), brine (50 mL), dried over MgSO₄ and concentrated invacuo to give a crude product which was further purified by columnchromatography (Ethyl acetate/Hexanes, 10%˜60%) ¹H NMR (400 MHz, CDCl₃)δ 4.70-4.60 (m, 1H), 3.90-3.78 (m, 2H), 2.22 (dd, J=5.9, 12.7, 1H),1.98-1.87 (m, 2H), 1.80 (dd, J=5.9, 12.7, 1H), 1.28 (d, J=4.8, 6H). ¹³CNMR (101 MHz, CDCl₃) δ 182.26, 75.01, 59.58, 43.93, 40.62, 38.69, 25.31,24.61; Rf, 0.34 (Hexane:Ethyl Acetate 1:1); Anal. Calcd for C₈H₁₄O₃: C,60.74; H, 8.92; Found: C, 60.47; H, 8.86.

The following compounds can be prepared by the procedure of5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one. The skilledpractitioner will know how to substitute the appropriate reagents,starting materials and purification methods known to those skilled inthe art, in order to prepare the compounds provided herein.

Example 7: Preparation of3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one: The title compoundwas prepared according to the procedure for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one, except ethyl2,2-diethylpent-4-enoate was substituted for methyl2,2-dimethylpent-4-enoate: ¹H NMR (400 MHz, CDCl₃) δ 4.62 (dtd, J=5.3,7.3, 9.5, 1H), 3.78 (t, J=6.1, 2H), 3.20 (s, 1H), 2.19 (dd, J=6.8, 13.1,1H), 1.97-1.81 (m, 3H), 1.70-1.56 (m, 4H), 0.93 (dt, J=7.5, 20.7, 6H);¹³C NMR (101 MHz, CDCl₃) δ 181.46, 75.10, 58.91, 48.77, 39.13, 37.76,29.21, 28.30, 8.83, 8.73; Rf, 0.36 (Hexane:Ethyl Acetate 5:2); Anal.Calcd for C₁₀H₁₃O₃: C, 64.49; H, 9.74; Found: C, 64.20; H, 9.57.

Example 8: Preparation of 7-(2-hydroxyethyl)-6-oxaspiro[3.4]octan-5-one:The title compound was prepared according to the procedure for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one, except1-allylcyclobutanecarboxylic acid was substituted for methyl2,2-dimethylpent-4-enoate: ¹H NMR (400 MHz, CDCl₃) δ 4.60-4.50 (m, 1H),3.82 (t, J=5.9, 2H), 2.61-2.40 (m, 3H), 2.19-1.96 (m, 5H). 1.92-185 (m,2H); ¹³C NMR (101 MHz, CDCl₃) δ 181.25, 75.46, 59.66, 44.62, 42.42,38.47, 31.95, 29.64, 16.79; Rf, 0.40 (Hexane:Ethyl Acetate 1:2); calcdfor C₉H₁₅O₃, 171.1021; found 171.1016.

Example 9: Preparation of 3-(2-hydroxyethyl)-2-oxaspiro[4.4]nonan-1-one:The title compound was prepared according to the procedure for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one, except1-allylcyclopentanecarboxylic acid was substituted for methyl2,2-dimethylpent-4-enoate: ¹H NMR (400 MHz, CDCl₃) δ 4.65-4.56 (m, 1H),3.84-3.76 (m, 2H), 2.74 (s, 1H), 2.28 (dd, J=5.8, 12.6, 1H), 2.20-2.10(m, 1H), 2.00-1.56 (m, 10H); ¹³C NMR (101 MHz, CDCl₃) δ 183.02, 75.77,59.20, 50.35, 43.41, 38.41, 37.49, 36.93, 25.67, 25.58; Rf, 0.46(Hexane:Ethyl Acetate 1:2); HRMS (CI): [M+H], calcd for C₁₀H₇₀₃,185.1178; found 185.1171.

Example 10: Preparation of3-(2-hydroxyethyl)-2-oxaspiro[4.5]decan-1-one: The title compound wasprepared according to the procedure for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one, except1-allylcyclohexanecarboxylic acid was substituted for methyl2,2-dimethylpent-4-enoate: ¹H NMR (400 MHz, CDCl₃) δ 4.62 (m, 1H), 3.82(t, J=5.9, 2H), 2.43 (dd, J=6.2, 12.9, 1H), 2.22 (s, 1H), 2.00-1.17 (m,13H). ¹³C NMR (101 MHz, CDCl₃) δ 181.96, 75.37, 59.55, 45.13, 39.88,38.91, 34.54, 31.71, 25.57, 22.42, 22.36; Rf, 0.46 (Hexane:Ethyl Acetate1:2); Anal. Calcd for C₁₁H₁₈O₃: C, 66.64; H, 9.15; Found: C, 66.48; H,9.17.

Example 11: Preparation of2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl4-methylbenzenesulfonate: To a stirred solution of5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one (0.316 g, 2 mmol,1.0 equiv) and triethylamine (0.152 g, 1.5 mmol, 1.5 equiv) in drydichloromethane, a solution of p-TosCl (0.475 g, 2.5 mmol, 1.25 equiv)in dichloromethane was added drop wise at 0° C. The resulting mixturewas stirred at 0° C. for 1 hour and allowed to stir overnight at roomtemperature. Then, the reaction mixture was diluted with dichloromethane(50 mL), washed with 10% HCl, brine, dried over MgSO₄ and concentratedin vacuo to afford yellowish oil. This crude product was then purifiedby flash chromatography (silica gel; Ethyl acetate/Hexanes, 0%˜40%) toafford desired tosylate. ¹H NMR (300 MHz, CDCl₃) δ 7.72 (m, 2H), 7.29(m, 2H), 4.39 (m, 1H), 4.10 (m, 2H), 2.38 (s, 3H), 2.09 (m, 1H), 1.93(m, 2H), 1.65 (m, 1H), 1.16 (d, J=4.8, 6H); ¹³C NMR (101 MHz, CDCl₃)¹³CNMR (101 MHz, CDCl3) δ 181.26, 145.16, 132.53, 130.03, 127.84, 77.68,77.36, 77.04, 72.93, 66.83, 42.99, 40.23, 34.97, 24.82, 24.12, 21.57;HRMS (CI): [M+H]313.1; Anal. Calcd for C₁₅H₂₀O₅S: C, 57.67; H, 6.45;Found: C, 57.85; H, 6.63.

The following compounds can be prepared by the procedure of2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl4-methylbenzenesulfonate. The skilled practitioner will know how tosubstitute the appropriate reagents, starting materials and purificationmethods known to those skilled in the art, in order to prepare thecompounds provided herein.

Example 12: Preparation of2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate:The title compound was prepared according to the procedure for2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl4-methylbenzenesulfonate, except3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one was substituted for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: ¹H NMR (300 MHz,CDCl₃) δ 7.79 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.55-4.33 (m,1H), 4.14 (dd, J=6.5, 13.3 Hz, 3H), 2.46 (s, 3H), 2.21-1.84 (m, 3H),1.83-1.68 (m, 1H), 1.58 (t, J=7.4 Hz, 4H), 0.89 (dt, J=7.5, 18.0 Hz,6H); ¹³C NMR (101 MHz, CDCl₃) δ 180.33, 145.30, 132.72, 130.15, 128.03,77.68, 77.36, 77.04, 73.18, 66.95, 48.67, 37.53, 35.82, 29.14, 28.23,21.76, 8.81, 8.74. Anal. Calcd for C₁₇H₂₄O₅S: C, 59.98; H, 7.11; Found:C, 60.27; H, 7.25.

Example 13: Preparation of 2-(5-oxo-6-oxaspiro[3.4]octan-7-yl)ethyl4-methylbenzenesulfonate: The title compound was prepared according tothe procedure for 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl4-methylbenzenesulfonate, except7-(2-hydroxyethyl)-6-oxaspiro[3.4]octan-5-one was substituted for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: ¹H NMR (400 MHz,CDCl₃) δ 7.77 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.37 (tdd,J=8.8, 6.0, 4.3 Hz, 1H), 4.21-4.05 (m, 2H), 2.57-2.32 (m, 6H), 2.19-1.82(m, 7H); ¹³C NMR (101 MHz, CDCl₃) δ 180.41, 145.24, 132.68, 130.10,128.02, 73.38, 66.76, 44.33, 41.79, 35.10, 31.72, 29.28, 21.76, 16.51.

Example 14: Preparation of 2-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)ethyl4-methylbenzenesulfonate: The title compound was prepared according tothe procedure for 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl4-methylbenzenesulfonate, except3-(2-hydroxyethyl)-2-oxaspiro[4.4]nonan-1-one was substituted for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: ¹H NMR (400 MHz,CDCl₃) δ 7.79 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.51-4.35 (m,1H), 4.25-4.06 (m, 2H), 2.45 (s, 3H), 2.28-2.08 (m, 2H), 2.08-1.91 (m,2H), 1.87-1.52 (m, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 181.90, 145.26,132.76, 130.12, 128.07, 73.71, 66.85, 50.19, 43.07, 37.44, 36.81, 35.19,25.61, 25.50, 21.79.

Example 15: Preparation of 2-(1-oxo-2-oxaspiro[4.5]decan-3-yl)ethyl4-methylbenzenesulfonate: The title compound was prepared according tothe procedure for 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl4-methylbenzenesulfonate, except3-(2-hydroxyethyl)-2-oxaspiro[4.5]decan-1-one was substituted for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: ¹H NMR (400 MHz,CDCl₃) δ 7.79 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.51-4.38 (m,1H), 4.26-4.12 (m, 2H), 2.45 (s, 3H), 2.36 (dd, J=12.9, 6.2 Hz, 1H),2.12-1.87 (m, 2H), 1.85-1.68 (m, 3H), 1.65-1.50 (m, 5H), 1.43-1.14 (m,3H); ¹³C NMR (101 MHz, CDCl₃) δ 180.97, 145.27, 132.76, 130.12, 128.07,73.28, 66.85, 44.96, 39.48, 35.58, 34.35, 31.52, 25.37, 22.23, 22.16,21.80.

Example 16: Preparation of5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one: To a solution of3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one (8.03 g, 43.0 mmol,1 eq.) in tetrahydrofuran (143 mL) was added triphenylphosphine (16.94g, 64.6 mmol, 1.5 eq.). The resulting solution was cooled to 0° C. andcarbon tetrabromide (21.44 g, 64.6 mmol, 1.5 eq.) was added in oneportion. The reaction was allowed to stir at 22° C. overnight. Thereaction mixture was diluted with ether and filtered and concentratedonto Celite in vacuo and further purified by column chromatography(ethyl acetate/hexanes, 0%˜30%, solid load). ¹H NMR (400 MHz, CDCl₃)δ4.60 (m, 1H), 3.53 (dd, J=5.5, 7.6 Hz, 2H), 2.27-2.07 (m, 3H), 1.82(dd, J=9.3, 13.0 Hz, 1H), 1.69-1.57 (m, 4H), 0.93 (dt, J=7.5, 25.7 Hz,6H).

Example 17: Preparation of 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one, except3-(2-hydroxyethyl)-2-oxaspiro[4.5]decan-1-one was substituted for3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one: ¹H NMR (400 MHz,CDCl₃) δ4.61 (m, 1H), 3.53 (dd, J=5.5, 7.6 Hz, 2H), 2.44 (dd, J=6.4,12.9 Hz, 1H), 2.29-2.07 (m, 2H), 1.88-1.70 (m, 3H), 1.69-1.54 (m, 4H),1.53-1.44 (m, 1H), 1.44-1.18 (m, 3H).

Example 18: Preparation of 2,2-diethylpent-4-enoic acid: Ethyl2,2-diethylpent-4-enoate (0.2 g, 0.28 mmol) is mixed with NaOH (0.4 g,10 mmol), MeOH (2.5 mL) and H₂O (2.5 mL) in a microwave vial. Themixture is then heated in a microwave reactor at 160° C. for 2 hours.The mixture was then acidified with 10% HCl, washed with ether (3×30ml). The combined organic phase was dried over MgSO₄ and concentrated invacuo to give a crude product which was used in the next step withoutfurther purification.

Example 19: Preparation of3,3-diethyl-5-(iodomethyl)dihydrofuran-2(3H)-one:2,2-diethylpent-4-enoic acid (1.77 g, 11.67 mmol) is stirred withtetrahydrofuran (34 mL), ether (12 mL) and saturated NaHCO₃ solution (57mL). The mixture is protected from sunlight. I2 was dissolved in 12 mLof tetrahydrofuran and added to the mixture in one portion at 0° C. Themixture was allowed to stir overnight at room temperature. Saturatedsodium thiosulfate is added to the mixture to quench the reaction. Themixture was extracted with ethyl acetate (3×50 mL). The combined organicphase was dried over MgSO₄ and concentrated in vacuo to give a crude oilwhich was purified by flash chromatography (silica gel; Ethylacetate/Hexanes, 0%˜25%). ¹H NMR (400 MHz, CDCl₃) δ 4.42 (dtd, J=9.0,7.3, 4.6 Hz, 1H), 3.41 (dd, J=10.2, 4.6 Hz, 1H), 3.23 (dd, J=10.2, 7.5Hz, 1H), 2.25 (dd, J=13.3, 6.9 Hz, 1H), 1.86 (dd, J=13.3, 9.1 Hz, 1H),1.63 (m, 4H), 0.94 (dt, J=10.4, 7.5 Hz, 6H). MS (LC/MS, M+H⁺): 283.0

The following compounds can be prepared by the procedure of3,3-diethyl-5-(iodomethyl)dihydrofuran-2(3H)-one. The skilledpractitioner will know how to substitute the appropriate reagents,starting materials and purification methods known to those skilled inthe art, in order to prepare the compounds provided herein.

Example 20: Preparation of 3-(iodomethyl)-2-oxaspiro[4.4]nonan-1-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(iodomethyl)dihydrofuran-2(3H)-one, except1-allylcyclopentanecarboxylic acid was substituted for2,2-diethylpent-4-enoic acid: ¹H NMR (400 MHz, CDCl₃) δ 4.48-4.34 (m,1H), 3.39 (dd, J=10.2, 4.9 Hz, 1H), 3.23 (dd, J=10.2, 7.5 Hz, 1H), 2.35(dd, J=12.9, 6.1 Hz, 1H), 2.20-2.04 (m, 1H), 1.93-1.54 (m, 8H); ¹³C NMR(101 MHz, CDCl₃) δ 181.57, 75.96, 50.71, 43.44, 37.84, 36.89, 25.45,25.36, 7.02; MS (LC/MS, M+H⁺): 281.0

Example 21: Preparation of 3-(iodomethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(iodomethyl)dihydrofuran-2(3H)-one, except1-allylcyclohexanecarboxylic acid was substituted for2,2-diethylpent-4-enoic acid: ¹H NMR (400 MHz, CDCl₃) δ 4.42 (dtd,J=9.2, 6.9, 4.6 Hz, 1H), 3.41 (dd, J=10.3, 4.6 Hz, 1H), 3.26 (dd,J=10.2, 7.3 Hz, 1H), 2.50 (dd, J=13.1, 6.5 Hz, 1H), 1.85-1.49 (m, 8H),1.44-1.20 (m, 3H); MS (LC/MS, M+H⁺): 295.0

Example 22: Preparation of 3-hydroxy-2-oxaspiro[4.4]nonan-1-one: To astirred mixture of 1-allylcyclopentanecarboxylic acid (10.93 g, 71 mmol,1 equiv), RuCl₃ stock solution (0.514 g, 0.035M in water, 0.035 equiv)and CH₃CN (500 mL), NaIO₄ (30.8 g, 142 mmol, 2.04 equiv) was added inportions over a period of 30 min at room temperature. The suspension wasallowed to stir at room temperature for another 30 min. The reaction wasquenched with saturated aqueous solution of Na₂S₂O₃ and the two layerswere separated. The aqueous layer was extracted with ethyl acetate(3×200 mL). The combined organic layer was washed with brine, dried overanhydrous MgSO₄, filtered, and concentrated. The residue was purified byflash column chromatography (silica gel; Ethyl acetate/Hexanes, 10%˜50%)to give desired product. ¹H NMR (400 MHz, CDCl₃) δ 5.87 (s, 1H), 5.28(s, 1H), 2.06 (dd, J=35.1, 28.9 Hz, 4H), 1.90-1.44 (m, 6H); ¹³C NMR (101MHz, CDCl₃) δ 183.20, 49.58, 43.94, 38.28, 25.42.

The following compounds can be prepared by the procedure of3-hydroxy-2-oxaspiro[4.4]nonan-1-one. The skilled practitioner will knowhow to substitute the appropriate reagents, starting materials andpurification methods known to those skilled in the art, in order toprepare the compounds provided herein.

Example 23: Preparation of 3-hydroxy-2-oxaspiro[4.5]decan-1-one: Thetitle compound was prepared according to the procedure for3-hydroxy-2-oxaspiro[4.4]nonan-1-one, except1-allylcyclohexanecarboxylic acid was substituted for1-allylcyclopentanecarboxylic acid: ¹H NMR (400 MHz, CDCl₃) δ 5.86 (t,J=4.5 Hz, 1H), 4.47 (broad, 1H), 2.18 (m, 2H), 1.83-1.43 (m, 7H), 1.32(d, J=5.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 181.91, 96.88, 44.52,40.54, 34.06, 25.28, 22.23.

Example 24: Preparation of 3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one:This reaction was performed in oven-dried glassware under a nitrogenatmosphere. To a well-stirred solution of freshly prepared but-1-enemagnesium bromide Grignard reagent (96 mmol, 1M, 3 equiv) in dry ether,3-hydroxy-2-oxaspiro[4.4]nonan-1-one (5.0 g, 32.0 mmol, 1.0 equiv) wasadded dropwise during 0.5 hours at 0° C. The reaction mixture wasstirred overnight at room temperature, quenched with 10% HCl (whilecooling in ice bath) until acidic (pH=2). The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (3×200mL). The extract was washed with 10% NaHCO₃ (100 mL) and brine (200 mL).The solution was then dried over MgSO₄, concentrated in vacuo andpurified by flash column chromatography (silica gel; Ethylacetate/Hexanes, 0%˜25%) to give desired product. ¹H NMR (400 MHz,CDCl₃) δ 5.79 (ddt, J=16.9, 10.2, 6.7 Hz, 1H), 5.15-4.88 (m, 2H), 4.36(ddt, J=9.7, 7.9, 5.5 Hz, 1H), 2.18 (m, 4H), 1.93-1.46 (m, 10H); ¹³C NMR(101 MHz, CDCl₃) δ 182.55, 137.26, 115.62, 77.19, 50.28, 43.24, 37.51,36.91, 34.83, 29.70, 25.56, 25.47.

The following compounds can be prepared by the procedure of3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one. The skilled practitionerwill know how to substitute the appropriate reagents, starting materialsand purification methods known to those skilled in the art, in order toprepare the compounds provided herein.

Example 25: Preparation of 3-(but-3-en-1-yl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one, except3-hydroxy-2-oxaspiro[4.5]decan-1-one was substituted for3-hydroxy-2-oxaspiro[4.4]nonan-1-one: ¹H NMR (400 MHz, CDCl₃) δ 5.80(ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.17-4.89 (m, 2H), 4.48-4.31 (m, 1H),2.36 (dd, J=12.9, 6.3 Hz, 1H), 2.30-2.08 (m, 2H), 1.87-1.17 (m, 13H);¹³C NMR (101 MHz, CDCl₃) δ 181.68, 137.31, 115.67, 76.77, 45.04, 39.55,35.31, 34.43, 31.70, 29.75, 25.42, 22.29, 22.22

Example 26: Preparation of 3-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)propyl4-methylbenzenesulfonate: To a stirred mixture of3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one (0.194 g, 1 mmol, 1 equiv),RuCl₃ stock solution (7.2 mg, 0.035M in water, 0.035 equiv) and CH₃CN (6mL), NaIO₄ (434 mg, 2.04 mmol, 2.04 equiv) was added in portions over aperiod of 5 min at room temperature. The suspension was allowed to stirat room temperature for another 30 min. The reaction was quenched withsaturated aqueous solution of Na₂S₂O₃ and the two layers were separated.The aqueous layer was extracted with ethyl acetate (3×20 mL). Thecombined organic layer was washed with brine, dried over anhydrousMgSO₄, filtered, and concentrated. The crude aldehyde was used for thenext step without further purification.

This reaction was performed in oven-dried glassware under a nitrogenatmosphere. To a well-stirred solution of the crude aldehyde (0.196 g, 1mmol, 1 equiv) in dry methanol, NaBH₄ (74 mg, 2.0 mmol, 2 equiv) wasadded to the mixture in one portion at 0° C. The reaction mixture wasstirred at room temperature for another 1 h, quenched with brine (whilecooling in ice bath). The organic layer was separated and the aqueouslayer was extracted with ethyl acetate (3×20 mL). The combined organicphase was then dried over MgSO₄, concentrated in vacuo. The crudealcohol was used for the next step without further purification.

To a stirred solution of the crude alcohol (0.396 g, 2 mmol, 1.0 equiv)and Et₃N (0.303 g, 3 mmol, 1.5 equiv) in dry dichloromethane, a solutionof p-TosCl (0.475 g, 2.5 mmol, 1.25 equiv) in dichloromethane was addeddrop wise at 0° C. The resulting mixture was stirred at 0° C. for 1 hourand allowed to stir overnight at room temperature. Then, the reactionmixture was diluted with dichloromethane (50 mL), washed with 10% HCl,brine, dried over MgSO₄ and concentrated in vacuo to afford yellowishoil. This crude product was then purified by flash chromatography(silica gel; Ethyl acetate/Hexanes, 0%˜40%) to afford desired tosylate.¹H NMR (400 MHz, CDCl₃) δ 7.82-7.71 (m, 2H), 7.35 (m, 2H), 4.37-4.23 (m,1H), 4.06 (qdd, J=10.0, 6.7, 5.2 Hz, 2H), 2.45 (s, 3H), 2.15 (m, 2H),1.92-1.50 (m, 12H); ¹³C NMR (101 MHz, CDCl₃) δ 182.29, 145.03, 133.05,130.04, 128.00, 76.90, 69.91, 50.24, 43.20, 37.53, 36.92, 31.74, 25.59,25.49, 25.37, 21.76.

The following compounds can be prepared by the procedure of3-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)propyl 4-methylbenzenesulfonate. Theskilled practitioner will know how to substitute the appropriatereagents, starting materials and purification methods known to thoseskilled in the art, in order to prepare the compounds provided herein.

Example 27: Preparation of 3-(1-oxo-2-oxaspiro[4.5]decan-3-yl)propyl4-methylbenzenesulfonate: The title compound was prepared according tothe procedure for 3-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)propyl4-methylbenzenesulfonate, except3-(but-3-en-1-yl)-2-oxaspiro[4.5]decan-1-one was substituted for3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one: ¹H NMR (400 MHz, CDCl₃) δ7.78 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.39-4.26 (m, 1H),4.16-3.97 (m, 2H), 2.44 (s, 3H), 2.32 (dt, J=15.8, 7.9 Hz, 1H),1.98-1.13 (m, 16H); ¹³C NMR (101 MHz, CDCl₃) δ 181.36, 145.03, 133.05,130.03, 127.99, 76.46, 69.91, 44.97, 39.54, 34.40, 32.15, 31.68, 25.37,25.36, 22.25, 22.18, 21.76

Example 28: Preparation of5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one:A solution of 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one (0.400g, 1.53 mmol, 1 eq.), acetonitrile (8 mL),2-benzyloctahydropyrrolo[3,4-c]pyrrole (0.340 g, 1.68 mmol, 1.1 eq.) andK₂CO₃ (1.05 g, 7.65 mmol, 5 eq.) was heated and stirred at 80° C. for 24hours. The resulting mixture was then filtered and concentrated in vacuoto give a crude residue that was further purified by columnchromatography (methanol/dichloromethane, 0%˜10%). ¹H NMR (400 MHz,CDCl₃) δ7.25-7.14 (m, 4H), 7.14-7.06 (m, 1H), 4.38 (m, 1H), 3.46 (s,2H), 2.64-2.48 (m, 6H), 2.48-2.38 (m, 2H), 2.28-2.13 (m, 4H), 2.02 (dd,J=6.8, 13.0 Hz, 1H), 1.87-1.59 (m, 3H), 1.58-1.44 (m, 4H), 0.83 (dt,J=7.3, 21.4 Hz, 6H); MS (LC/MS, M+H⁺): m/z 371.2

Example 29: Preparation of3-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one,except 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one was substituted for5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one: ¹H NMR (400 MHz,CDCl₃) δ7.26-7.17 (m, 4H), 7.17-7.10 (m, 1H), 4.40 (m, 1H), 3.50 (s,2H), 2.69-2.52 (m, 6H), 2.49 (t, J=7.4 Hz, 2H), 2.30 (dd, J=6.3, 12.8Hz, 1H), 2.27-2.16 (m, 4H), 1.88-1.61 (m, 5H), 1.61-1.45 (m, 4H),1.44-1.37 (m, 1H), 1.36-1.07 (m, 3H); MS (LC/MS, M+H⁺): m/z 383.2

Example 30: Preparation of3,3-diethyl-5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:A mixture of5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one(540 mg, 1.46 mmol, 1 eq.), Pd/C (108 mg, 20% wt) and MeOH (5.0 mL) wasstirred at 22° C. under 1 atm of H₂ (filled balloon) for 3 days. Themixture was filtered through a plug of Celite, washed with MeOH (50 mL)and concentrated in vacuo to give a crude product that was used infollowing steps without further purification. ¹H NMR (400 MHz, CDCl₃)δ4.42 (m, 1H), 2.83 (b, 1H), 2.69 (m, 2H), 2.55-2.39 (m, 4H), 2.33 (m,2H), 2.26 (t, J=7.0 Hz, 2H), 2.14 (dd, J=1.7, 9.0 Hz, 2H), 1.91 (dd,J=6.7, 13.0 Hz, 1H), 1.71-1.47 (m, 3H), 1.45-1.32 (m, 4H), 0.69 (dt,J=7.4, 19.2 Hz, 6H); MS (LC/MS, M+H⁺): m/z 281.2

Example 31: Preparation of3-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except3-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-onewas substituted for5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one:¹H NMR (400 MHz, CDCl₃) δ4.55 (m, 1H), 2.94 (m, 2H), 2.82-2.63 (m, 5H),2.63-2.46 (m, 3H), 2.42 (m, 2H), 1.97-1.60 (m, 8H), 1.59-1.43 (m, 3H),1.43-1.22 (m, 4H); MS (LC/MS, M+H⁺): m/z 293.2

Example 32: Preparation of3,3-diethyl-5-(2-(5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:A solution of3,3-diethyl-5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one(0.180 g, 0.642 mmol, 1 eq.), 1-butanol (6.4 mL), 4-bromopyridinehydrochloride (0.249 g, 1.28 mmol, 2.0 eq.) and triethylamine (0.325 g,3.21 mmol, 5 eq.) was heated and stirred at 120° C. for 24 hours. Theresulting solution was concentrated in vacuo to give a crude residuethat was further purified by column chromatography(methanol/dichloromethane, 0%˜10%, w/0.1% NH₄OH). ¹H NMR (400 MHz,CDCl₃) δ8.13 (dd, J=1.4, 3.5 Hz, 2H), 6.32 (dd, J=1.5, 3.5 Hz, 2H), 4.37(m, 1H), 3.45 (dd, J=8.3, 9.2 Hz, 2H), 3.12 (dt, J=3.4, 9.9 Hz, 2H),2.90 (m, 2H), 2.62 (m, 2H), 2.50 (t, J=7.4 Hz, 2H), 2.46 (m, 2H), 2.02(dd, J=6.8, 13.0 Hz, 1H), 1.85-1.61 (m, 3H), 1.52 (q, J=7.5 Hz, 4H),0.82 (dt, J=5.7, 13.2 Hz, 6H); MS (LC/MS, M+H⁺): m/z 358.2

Example 33: Preparation of3-(2-(5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except3-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-onewas substituted for3,3-diethyl-5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:¹H NMR (400 MHz, CDCl₃) δ8.13 (d, J=5.6 Hz, 2H), 6.33 (d, J=6.2 Hz, 2H),4.38 (m, 1H), 3.46 (m, 2H), 3.13 (dt, J=3.7, 10.0 Hz, 2H), 2.91 (m, 2H),2.68-2.57 (m, 2H), 2.55-2.41 (m, 4H), 2.28 (dd, J=6.2, 12.8 Hz, 1H),1.95-1.43 (m, 9H), 1.43-1.33 (m, 1H), 1.32-1.04 (m, 3H); MS (LC/MS,M+H⁺): m/z 370.2.

Example 34: Preparation of 1-(benzyloxy)-2-bromobenzene: To a solutionof 2-bromophenol (1.0 g, 5.78 mmol, 1.01 eq.) in acetonitrile (14 mL)was added benzyl bromide (0.975 g, 5.7 mmol, 1.0 eq.) and K₂CO₃ (1.09 g,7.87 mmol, 1.38 eq.). This mixture was allowed to stir at 22° C.overnight. The reaction was filtered and concentrated in vacuo to give acrude residue that was further purified by column chromatography(hexanes/ethyl acetate, 0%˜10%). ¹H NMR (400 MHz, CDCl₃) δ7.60 (dd,J=1.6, 7.8 Hz, 1H), 7.51 (m, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.35 (m, 1H),7.29-7.22 (m, 1H), 6.97 (dd, J=1.2 8.3 Hz, 1H), 6.88 (td, J=1.3, 7.6 Hz,1H), 5.19 (s, 2H).

Example 35: Preparation of 1-(benzyloxy)-3-bromobenzene: The titlecompound was prepared according to the procedure for1-(benzyloxy)-2-bromobenzene, except 3-bromophenol was substituted for2-bromophenol: ¹H NMR (400 MHz, CDCl₃) δ7.50-7.34 (m, 5H), 7.23-7.10 (m,3H), 6.95 (m, 1H), 5.08 (s, 2H).

Example 36: Preparation of 1-(benzyloxy)-4-bromobenzene: The titlecompound was prepared according to the procedure for1-(benzyloxy)-2-bromobenzene, except 4-bromophenol was substituted for2-bromophenol: ¹H NMR (400 MHz, CDCl₃) δ7.51-7.33 (m, 7H), 6.91 (d,J=9.1 Hz, 2H), 5.08 (s, 2H).

Example 37: Preparation of 4-(2-bromophenyl)morpholine: This reactionwas performed in oven-dried glassware under a nitrogen atmosphere. To asolution of 1,2-dibromobenzene (1.0 g, 4.24 mmol, 1.0 eq.) andmorpholine (0.370 g, 4.24 mmol, 1.0 eq.) in anhydrous toluene (10.6 mL)was added the following in this order: Pd₂(dba)₃ (0.097 g, 5 mol %),BINAP (0.197 g, 7.5 mol %), and NaOtBu (0.448 g, 5.08 mmol, 1.2 eq.).The resulting mixture was allowed to stir at 80° C. overnight, under asweep of N₂. The reaction mixture was cooled to 22° C. and then filteredthrough a plug of Celite. The collected filtrate was concentrated invacuo to give a crude residue that was further purified by columnchromatography (hexanes/ethyl acetate, 0%˜20%). ¹H NMR (400 MHz, CDCl₃)δ7.55 (dd, J=1.5, 7.9 Hz, 1H), 7.25 (td, J=1.4, 7.8 Hz, 1H), 7.00 (dd,J=1.4, 8.0 Hz, 1H), 6.89 (td, J=1.4, 7.7 Hz, 1H), 3.83 (m, 4H), 2.99 (m,4H); MS (LC/MS, M+H⁺): m/z 241.9, 243.8

Example 38: Preparation of tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate: This reaction wasperformed in oven-dried glassware under a nitrogen atmosphere. To asolution of 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butylester hemioxylate (0.300 g, 1.23 mmol, 1.1 eq.) and bromobenzene (0.176g, 1.12 mmol, 1.0 eq.) in anhydrous toluene (14 mL) was added thefollowing in this order: Pd₂(dba)₃ (0.030 g, 2.5 mol %), BINAP (0.0450g, 1.5/Pd), triethylamine (0.125 g, 1.23 mmol, 1.1 eq.) and NaOtBu(0.355 g, 3.69 mmol, 3.3 eq.). The resulting mixture was allowed to stirat 110° C. overnight, under a sweep of N₂. The reaction mixture wascooled to 22° C. and then filtered through a plug of Celite. Thecollected filtrate was concentrated in vacuo to give a crude residuethat was further purified by column chromatography (hexanes/ethylacetate, 0%˜30%). ¹H NMR (400 MHz, CDCl₃) δ7.21 (m, 2H), 6.93 (m, 1H),6.74 (d, J=8.3 Hz, 2H), 4.23 (s, 4H), 4.19 (s, 4H), 1.38 (s, 9H); MS(LC/MS, M+H⁺): m/z 275.2

Example 39: Preparation of tert-butyl6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate: The titlecompound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except4-bromopyridine hydrochloride was substituted for bromobenzene and 2equivalents of triethylamine was utilized: ¹H NMR (400 MHz, CDCl₃) δ8.09(d, J=6.5 Hz, 2H), 6.28 (d, J=6.7 Hz, 2H), 4.12 (s, 4H), 4.06 (s, 4H),1.37 (s, 9H); MS (LC/MS, M+H⁺): m/z 276.2

Example 40: Preparation of tert-butyl6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except4-bromo-3-methylpyridine hydrochloride was substituted for bromobenzeneand 2 equivalents of triethylamine was utilized: ¹H NMR (400 MHz, CDCl₃)δ8.05 (d, J=5.5 Hz, 1H), 7.94 (s, 1H), 6.12 (d, J=5.4 Hz, 1H), 4.08 (s,4H), 4.02 (s, 4H), 2.10 (s, 3H) 1.37 (s, 9H); MS (LC/MS, M+H⁺): m/z290.2

Example 41: Preparation of tert-butyl6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except4-bromo-2-methylpyridine was substituted for bromobenzene: ¹H NMR (400MHz, CDCl₃) δ8.05 (d, J=5.5 Hz, 1H), 6.07-6.00 (m, 2H), 4.02 (s, 4H),3.95 (s, 4H), 2.35 (s, 3H), 1.37 (s, 9H); MS (LC/MS, M+H⁺): m/z 290.2

Example 42: Preparation of tert-butyl6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate:The title compound was prepared according to the procedure fortert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except4-bromo-2,6-dimethylpyridine was substituted for bromobenzene: ¹H NMR(400 MHz, CDCl₃) δ 5.90 (s, 2H), 4.01 (s, 4H), 3.92 (s, 4H), 2.32 (s,6H), 1.37 (s, 9H); MS (LC/MS, M+H*j m/z 304.2

Example 43: Preparation of tert-butyl5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate:The title compound was prepared according to the procedure fortert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, excepttert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butylester hemioxylate, 4-bromo-3-methylpyridine hydrochloride wassubstituted for bromobenzene and 2 equivalents of triethylamine wasutilized: ¹H NMR (400 MHz, CDCl₃) δ8.03 (d, J=5.8 Hz, 1H), 7.97 (s, 1H),6.37 (d, J=5.8 Hz, 1H), 3.64-3.44 (m, 4H), 3.33-3.10 (m, 4H), 2.86 (b,2H), 2.24 (s, 3H), 1.38 (s, 9H); MS (LC/MS, M+H⁺): m/z 304.2

Example 44: Preparation of tert-butyl5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate:The title compound was prepared according to the procedure fortert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, excepttert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butylester hemioxylate and 4-bromo-2-methylpyridine was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.99 (d, J=5.9 Hz, 1H), 6.13 (d,J=2.2 Hz, 1H), 6.09 (dd, J=2.4, 5.8 Hz, 1H), 3.54 (dd, J=7.2, 11.2 Hz,2H), 3.42 (b, 2H), 3.21 (m, 1H), 3.17-2.99 (m, 3H), 2.88 (b, 2H), 2.32(s, 3H), 1.36 (s, 9H); MS (LC/MS, M+H⁺): m/z 304.2

Example 45: Preparation of tert-butyl5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate:The title compound was prepared according to the procedure fortert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, excepttert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butylester hemioxylate and 4-bromo-2,6-dimethylpyridine was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ5.98 (s, 2H), 3.52 (m, 2H), 3.41(m, 2H), 3.21 (m, 1H), 3.16-2.99 (m, 3H), 2.86 (b, 2H), 2.29 (s, 6H),1.34 (s, 9H); MS (LC/MS, M+H⁺): m/z 318.2.

Example 46: Preparation of tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: The titlecompound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-2-methylbenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.18-7.10 (m, 2H), 6.96-6.89 (m,2H), 3.69 (b, 2H), 3.36 (b, 2H), 3.18 (b, 2H), 3.05 (b, 2H), 2.91 (b,2H), 2.33 (s, 3H), 1.52 (s, 9H); MS (LC/MS, M+H⁺): m/z 303.2

Example 47: Preparation of tert-butyl5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: The titlecompound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-3-methylbenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.17 (t, J=7.8 Hz, 1H), 6.59 (d,J=7.5 Hz, 1H), 6.46-6.37 (m, 2H), 3.68 (b, 2H), 3.52 (b, 2H), 3.42 (m,1H), 3.29 (m, 1H), 3.23 (m, 2H), 2.97 (b, 2H), 2.38 (s, 3H), 1.54 (s,9H); MS (LC/MS, M+H⁺): m/z 303.2

Example 48: Preparation of tert-butyl5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: The titlecompound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-4-methylbenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.09 (d, J=8.1 Hz, 2H), 6.52 (d,J=8.5 Hz, 2H), 3.68 (m, 2H), 3.57 (b, 2H), 3.42 (m, 1H), 3.28 (m, 1H),3.21 (m, 2H), 3.00 (b, 2H), 2.30 (s, 3H), 1.51 (s, 9H); MS (LC/MS,M+H⁺): m/z 303.2.

Example 49: Preparation of tert-butyl5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-2-methoxybenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ6.91-6.78 (m, 3H), 6.76-6.67 (m,1H), 3.80 (s, 3H), 3.61 (b, 2H), 3.45 (b, 2H), 3.40-3.22 (m, 2H), 3.14(b, 2H), 2.90 (b, 2H), 1.46 (s, 9H); MS (LC/MS, M+H⁺): m/z 319.2.

Example 50: Preparation of tert-butyl5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-3-methoxybenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.13 (t, J=8.1 Hz, 1H), 6.29 (dd,J=2.2, 8.1 Hz, 1H), 6.18 (dd, J=1.8, 8.1 Hz, 1H), 6.10 (t, J=2.2 Hz,1H), 3.79 (s, 3H), 3.63 (m, 2H), 3.50 (m, 2H), 3.37 (m, 1H), 3.30-3.11(m, 3H), 2.95 (b, 2H), 1.48 (s, 9H); MS (LC/MS, M+H⁺): m/z 319.2

Example 51: Preparation of tert-butyl5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-4-methoxybenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ6.83 (d, J=9.0 Hz, 2H), 6.50 (d,J=9.0 Hz, 2H), 3.73 (s, 3H), 3.62 (m, 2H), 3.48-3.29 (m, 3H), 3.23 (m,1H), 3.12 (dd, J=3.5, 9.3 Hz, 2H), 2.93 (b, 2H), 1.46 (s, 9H); MS(LC/MS, M+H⁺): m/z 319.2.

Example 52: Preparation of tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 2-bromobenzonitrile was substituted for bromobenzene: ¹HNMR (400 MHz, CDCl₃) δ7.39 (dd, J=1.6, 7.8 Hz, 1H), 7.30 (m, 1H), 6.66(t, J=7.5 Hz, 1H), 6.59 (d, J=8.5 Hz, 1H), 3.80 (m, 2H), 3.61 (m, 2H),3.52 (m, 1H), 3.44 (m, 1H), 3.28 (m, 2H), 2.95 (b, 2H), 1.42 (s, 9H); MS(LC/MS, M+H⁺): m/z 314.2.

Example 53: Preparation of tert-butyl5-(3-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 3-bromobenzonitrile was substituted for bromobenzene: ¹HNMR (400 MHz, CDCl₃) δ7.22 (m, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.71-6.64(m, 2H), 3.62 (m, 2H), 3.49 (m, 2H), 3.31 (m, 1H), 3.23 (m, 1H), 3.16(dd, J=3.9, 9.7 Hz, 2H), 2.99 (b, 2H), 1.42 (s, 9H); MS (LC/MS, M+H⁺):m/z 314.2

Example 54; Preparation of tert-butyl5-(4-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 4-bromobenzonitrile was substituted for bromobenzene: ¹HNMR (400 MHz, CDCl₃) δ7.35 (d, J=8.9 Hz, 2H), 6.41 (d, J=8.9 Hz, 2H),3.57 (m, 2H), 3.50 (m, 2H), 3.26 (m, 1H), 3.21-3.06 (m, 3H), 2.95 (b,2H), 1.37 (s, 9H); MS (LC/MS, M+H⁺): m/z 314.2.

Example 55: Preparation of tert-butyl5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate:The title compound was prepared according to the procedure fortert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, excepttert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butylester hemioxylate and 1-(benzyloxy)-2-bromobenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.36-7.23 (m, 4H), 7.20 (m, 1H),6.79 (m, 2H), 6.72 (m, 1H), 6.65 (m, 1H), 4.94 (s, 2H), 3.50 (b, 2H),3.33 (m, 2H), 3.27-3.02 (m, 3H), 2.76 (b, 2H), 1.35 (s, 9H); MS (LC/MS,M+H⁺): m/z 395.2.

Example 56: Preparation of tert-butyl5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate:The title compound was prepared according to the procedure fortert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, excepttert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butylester hemioxylate and 1-(benzyloxy)-3-bromobenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.47 (m, 2H), 7.41 (t, J=7.6 Hz,2H), 7.34 (m, 1H), 7.17 (t, J=8.2 Hz, 1H), 6.39 (dd, J=1.7, 8.0 Hz, 1H),6.23 (m, 2H), 5.08 (s, 2H), 3.66 (m, 2H), 3.53 (m, 2H), 3.40 (m, 1H),3.33-3.14 (m, 3H), 2.99 (b, 2H), 1.49 (s, 9H); MS (LC/MS, M+H⁺): m/z395.2.

Example 57: Preparation of tert-butyl5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate:The title compound was prepared according to the procedure fortert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, excepttert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butylester hemioxylate and 1-(benzyloxy)-4-bromobenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.46 (m, 2H), 7.40 (t, J=7.8 Hz,2H), 7.34 (m, 1H), 6.95 (d, J=9.0 Hz, 2H), 6.54 (d, J=8.8 Hz, 2H), 5.03(s, 2H), 3.67 (b, 2H), 3.47 (b, 2H), 3.40 (m, 1H), 3.28 (m, 1H), 3.18(dd, J=3.4, 9.3 Hz, 2H), 2.99 (b, 2H), 1.50 (s, 9H); MS (LC/MS, M+H⁺):m/z 395.2.

Example 58: Preparation of tert-butyl5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate:The title compound was prepared according to the procedure fortert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, excepttert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butylester hemioxylate and 4-(2-bromophenyl)morpholine was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.04-6.89 (m, 3H), 6.85 (d, J=7.8Hz, 1H), 3.85 (t, J=4.5 Hz, 4H), 3.62 (b, 2H), 3.48-3.21 (m, 6H), 3.04(t, J=4.5 Hz, 4H), 2.92 (b, 2H), 1.48 (s, 9H); MS (LC/MS, M+H⁺): m/z374.2.

Example 59: Preparation of2-benzyl-5-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole: The titlecompound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except2-benzyloctahydropyrrolo[3,4-c]pyrrole was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-2-isopropylbenzene was substituted forbromobenzene. The product was purified by column chromatography(dichloromethane/MeOH, 0%˜5%). ¹H NMR (400 MHz, CDCl₃) δ7.54-7.33 (m,6H), 7.32-7.11 (m, 3H), 3.77 (s, 2H), 3.65 (sept, J=6.9 Hz, 1H), 3.15(m, 2H), 3.09-2.99 (m, 4H), 2.96 (m, 2H), 2.47 (dd, J=4.9, 8.8 Hz, 2H),1.39 (d, J=6.9 Hz, 9H) MS (LC/MS, M+H⁺): m/z 321.2.

Example 60: Preparation of 2-phenyl-2,6-diazaspiro[3.3]heptanetrifluoroacetate: To a solution of tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.054 g, 0.196 mmol,1 eq.) in dichloromethane (1 mL) at 0° C. was added trifluoroacetic acid(1 mL). The reaction was allowed to stir at 22° C. for 30 minutes beforebeing diluted with MeOH and concentrated in vacuo to afford the productas a TFA salt. MS (LC/MS, M+H⁺): m/z 175.2.

Example 61: Preparation of 2-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptaneditrifluoroacetate: The title compound was prepared according to theprocedure for 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate,except tert-butyl6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate wassubstituted for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate: MS (LC/MS, M+H⁺): m/z176.2.

Example 62: Preparation of2-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane ditrifluoroacetate:The title compound was prepared according to the procedure for2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate, except tert-butyl6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate wassubstituted for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate: MS (LC/MS, M+H⁺): m/z190.2.

Example 63: Preparation of2-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane ditrifluoroacetate:The title compound was prepared according to the procedure for2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate, except tert-butyl6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate wassubstituted for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate: MS (LC/MS, M+H⁺): m/z190.2.

Example 64: Preparation of2-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane: The titlecompound was prepared according to the procedure for2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate, except tert-butyl6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylatewas substituted for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate: MS (LC/MS, M+H⁺): m/z204.2.

Example 65: Preparation of2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrroleditrifluoroacetate: The title compound was prepared according to theprocedure for 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate,except tert-butyl5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewas substituted for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate: MS (LC/MS, M+H⁺): m/z204.2.

Example 66: Preparation of2-(2-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrroleditrifluoroacetate: The title compound was prepared according to theprocedure for 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate,except tert-butyl5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewas substituted for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate: MS (LC/MS, M+H⁺): m/z204.2.

Example 67: Preparation of2-(2,6-dimethylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole: The titlecompound was prepared according to the procedure for2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate, except tert-butyl5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewas substituted for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate: MS (LC/MS, M+H⁺): m/z218.2.

Example 68: Preparation of 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: Toa solution of tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.490 g,1.62 mmol, 1 eq.) in dichloromethane (4 mL) at 0° C. was addedtrifluoroacetic acid (2 mL). The reaction was allowed to stir at 22° C.for 30 minutes before being diluted with MeOH and concentrated in vacuoto afford the product as a TFA salt. The salt was then suspended in sat.NaHCO₃ solution and the free based product was extracted with methylenechloride (3×15 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentration in vacuo to afford the product as a freebase: MS (LC/MS, M+H⁺): m/z 203.2.

Example 69: Preparation of 2-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole:The title compound was prepared according to the procedure for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except tert-butyl5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS (LC/MS,M+H⁺): m/z 203.2.

Example 70: Preparation of 2-(p-tolyl)octahydropyrrolo[3,4-c]pyrrole:The title compound was prepared according to the procedure for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS (LC/MS,M+H⁺): m/z 203.2

Example 71: Preparation of2-(2-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole: The title compoundwas prepared according to the procedure for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except tert-butyl5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS (LC/MS,M+H⁺): m/z 219.2.

Example 72: Preparation of2-(4-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole: The title compoundwas prepared according to the procedure for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except tert-butyl5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS (LC/MS,M+H⁺): m/z 219.2.

Example 73: Preparation of3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile: The titlecompound was prepared according to the procedure for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except tert-butyl5-(3-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS (LC/MS,M+H⁺): m/z 214.2

Example 74: Preparation of4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile: The titlecompound was prepared according to the procedure for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except tert-butyl5-(4-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS (LC/MS,M+H⁺): m/z 214.2.

Example 75: Preparation of2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride: Toa solution of tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.408g, 1.30 mmol, 1 eq.) in MeOH (1 mL) at 0° C. was added 1M methanolic HCl(3 mL). The reaction was allowed to stir at 22° C. overnight beforebeing diluted with MeOH and concentrated in vacuo to afford the productas a HCl salt. MS (LC/MS, M+H⁺): m/z 214.2.

Example 76: Preparation of2-(3-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride: Thetitle compound was prepared according to the procedure for2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride,except tert-butyl5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS(LC/MS, M+H⁺): m/z 219.2.

Example 77: Preparation of2-(2-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride: Thetitle compound was prepared according to the procedure for2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride,except tert-butyl5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewas substituted for tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS(LC/MS, M+H⁺): m/z 295.2.

Example 78: Preparation of2-(3-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride: Thetitle compound was prepared according to the procedure for2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride,except tert-butyl5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewas substituted for tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS(LC/MS, M+H⁺): m/z 295.2.

Example 79: Preparation of2-(4-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride: Thetitle compound was prepared according to the procedure for2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride,except tert-butyl5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewas substituted for tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS(LC/MS, M+H⁺): m/z 295.2.

Example 80: Preparation of4-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)morpholinehydrochloride: The title compound was prepared according to theprocedure for 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrilehydrochloride, except tert-butyl5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewas substituted for tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS(LC/MS, M+H⁺): m/z 274.2.

Example 81: Preparation of2-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole: To a dry roundbottom flask, 0.04 g of 10% Pd/C (20% wt) was added and wet with a smallamount of ethyl acetate. Following, a solution of2-benzyl-5-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole (0.20 g,0.624 mmol, 1 eq.) in MeOH (2.1 mL) was added slowly to the Pd/Ccontaining round bottom flask. This system was then flushed 3× with H₂,using a balloon filled with H₂. The reaction was allowed to stir under 1atm H₂ for 5 days at room temperature. The Pd/C was removed viafiltration through a plug of Celite. The filtrate was concentrated invacuo to afford a crude oil of2-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole which was used inthe next step without further purification. MS (LC/MS, M+H⁺): m/z 231.2.

Example 82: Preparation of3-(2-(6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-onetrifluoroacetate: A mixture of3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one (0.057 g, 0.221 mmol, 1eq.), acetonitrile (2 mL), 2-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptaneditrifluoroacetate (0.098 g, 0.266 mmol, 1.2 eq.) and K₂CO₃ (0.153 g,1.11 mmol, 5 eq.) was refluxed and stirred for 3 days. The resultingmixture was then filtered and concentrated in vacuo to give a cruderesidue that was first purified by column chromatography(methanol/dichloromethane, 0%˜10% w/0.1% NH₄OH). The resulting fractionswere further purified by column chromatography on a C18 column.(acetonitrile/H₂O, 0%˜100%, w/0.1% TFA) ¹H NMR (400 MHz, MeOD) δ8.11 (d,J=7.4 Hz, 2H), 6.67 (d, J=7.1 Hz, 2H), 4.70-4.17 (b, 9H), 3.44 (m, 2H),2.54 (dd, J=6.2, 12.9 Hz, 1H), 2.10-1.99 (m, 1H), 1.98-1.86 (m, 1H),1.83-1.61 (m, 6H), 1.60-1.44 (m, 3H), 1.43-1.21 (m, 2H); MS (LC/MS,M+H⁺): =356.2.

Example 83: Preparation of3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one:A mixture of 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one (0.080g, 0.324 mmol, 1 eq.), acetonitrile (2 mL),2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate (0.288 g, 0.389mmol, 1.2 eq.) and K₂CO₃ (0.224 g, 1.62 mmol, 5 eq.) was refluxed andstirred for 3 days. The resulting mixture was then filtered andconcentrated in vacuo to give a crude residue that was first purified bycolumn chromatography (methanol/dichloromethane, 0%˜10%). ¹H NMR (400MHz, CDCl₃) δ7.13 (m, 2H), 6.67 (t, J=7.4 Hz, 1H), 6.37 (d, J=8.2 Hz,2H), 4.36 (m, 1H), 3.85 (s, 4H), 3.29 (s, 4H), 2.48 (t, J=7.1 Hz, 2H),2.04 (dd, J=6.7, 13.0 Hz, 1H), 1.71 (dd, J=9.4, 13.1 Hz, 1H), 1.67-1.43(m, 6H), 1.83-1.61 (m, 6H), 0.85 (dt, J=7.5, 21.9 Hz, 6H); MS (LC/MS,M+H⁺): 343.2.

Example 84: Preparation of3-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one,except 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one was substituted for5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one: ¹H NMR (400 MHz,CDCl₃) δ7.13 (m, 2H), 6.67 (t, J=7.4 Hz, 1H), 6.37 (d, J=8.5 Hz, 2H),4.38 (m, 1H), 3.86 (s, 4H), 3.29 (s, 4H), 2.50 (t, J=7.9 Hz, 2H), 2.30(dd, J=6.2, 12.9 Hz, 1H), 1.81-1.45 (m, 9H), 1.45-1.37 (m, 1H),1.37-1.08 (m, 3H); MS (LC/MS, M+H⁺): m/z 355.2.

Example 85: Preparation of3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole wassubstituted for 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate: ¹HNMR (400 MHz, CDCl₃) δ7.18 (dd, J=1.5, 7.4 Hz, 1H), 7.10-6.90 (m, 3H),4.43 (m, 1H), 3.38 (sept, J=6.9 Hz, 1H), 3.01-2.84 (m, 4H), 2.83-2.66(m, 4H), 2.52 (t, J=6.8 Hz, 2H), 2.19 (m, 2H), 2.06 (dd, J=6.8, 13.1 Hz,1H), 1.91-1.67 (m, 3H), 1.63-1.44 (m, 4H), 1.15 (d, J=6.9 Hz, 6H), 0.86(dt, J=7.3, 19.3 Hz, 6H); MS (LC/MS, M+H⁺): m/z 399.2.

Example 86: Preparation of3-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one,except 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one was substituted for5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one and2-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole was substituted for2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate: ¹H NMR (400 MHz,CDCl₃) δ7.18 (dd, J=1.5, 7.0 Hz, 1H), 7.09-6.94 (m, 3H), 4.44 (m, 1H),3.37 (sept, J=6.8 Hz, 1H), 2.99-2.83 (m, 4H), 2.82-2.66 (m, 4H), 2.52(t, J=7.2 Hz, 2H), 2.32 (dd, J=6.3, 12.7 Hz, 1H), 2.24-2.12 (m, 2H),1.93-1.81 (m, 1H), 1.80-1.46 (m, 8H), 1.46-1.37 (m, 1H), 1.37-1.04 (m,9H) MS (LC/MS, M+H⁺): m/z 411.2.

Example 87: Preparation of3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:A mixture of 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one (0.100 g, 0.383mmol, 1 eq.), acetonitrile (4 mL),2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrroleditrifluoroacetate (0.299 g, 0.766 mmol, 2 eq.) and K₂CO₃ (0.264 g, 1.91mmol, 5 eq.) was refluxed and stirred for 3 days. The resulting mixturewas then filtered and concentrated in vacuo to give a crude residue thatwas first purified by column chromatography on a C18 column.(acetonitrile/H₂O, 0%˜100%, w/0.1% NH₄OH). The resulting fractions werefurther purified by column chromatography (methanol/dichloromethane,0%˜10% w/0.1% NH₄OH). ¹H NMR (400 MHz, CDCl₃) δ8.06 (d, J=18.7 Hz, 2H),6.49 (d, J=4.7 Hz, 1H), 4.38 (m, 1H), 3.20 (m, 2H), 3.04 (m, 2H),2.83-2.66 (m, 4H), 2.47 (m, 2H), 2.35-2.21 (m, 3H), 2.17 (s, 3H),1.85-1.74 (m, 1H), 1.74-1.40 (m, 8H), 1.40-1.32 (m, 1H), 1.31-1.02 (m,3H); MS (LC/MS, M+H⁺): m/z 384.2.

Example 88: Preparation of3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one,except 2-(2-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrroleditrifluoroacetate was substituted for2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrroleditrifluoroacetate: ¹H NMR (400 MHz, CDCl₃) δ7.99 (d, J=5.4 Hz, 1H),6.23-6.07 (m, 2H), 4.35 (m, 1H), 3.40 (t, J=8.5 Hz, 2H), 3.08 (dt,J=3.3, 9.9 Hz, 2H), 2.85 (b, 2H), 2.65-2.53 (m, 2H), 2.52-2.36 (m, 4H),2.32 (s, 3H), 2.25 (dd, J=6.3, 12.8 Hz, 1H), 1.84-1.39 (m, 9H),1.39-1.29 (m, 1H), 1.28-1.01 (m, 3H); MS (LC/MS, M+H⁺): m/z 384.2

Example 89: Preparation of3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one,except2-(2,6-dimethylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrroleditrifluoroacetatewas substituted for2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrroleditrifluoroacetate: ¹H NMR (400 MHz, CDCl₃) δ6.02 (s, 2H), 4.35 (m, 1H),3.38 (m, 2H), 3.08 (dt, J=3.1, 9.9 Hz, 2H), 2.84 (b, 2H), 2.68-2.53 (m,2H), 2.53-2.36 (m, 4H), 2.36-2.17 (m, 7H), 1.84-1.39 (m, 9H), 1.38-1.30(m, 1H), 1.28-0.97 (m, 3H); MS (LC/MS, M+H⁺): m/z 398.2.

Example 90: Preparation of3-(2-(6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one,except 2-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptaneditrifluoroacetate was substituted for2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrroleditrifluoroacetate: ¹H NMR (400 MHz, CDCl₃) δ8.02 (d, J=5.2 Hz, 1H),7.90 (s, 1H), 6.11 (d, J=5.6 Hz, 1H), 4.38 (m, 1H), 4.06 (s, 4H), 3.29(s, 4H), 2.49 (t, J=7.8 Hz, 2H), 2.30 (dd, J=6.2, 12.9 Hz, 1H), 2.11 (s,3H), 1.83-1.45 (m, 9H), 1.45-1.37 (m, 1H), 1.37-1.08 (m, 3H); MS (LC/MS,M+H⁺): m/z 370.2.

Example 91: Preparation of3-(2-(6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one,except 2-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptaneditrifluoroacetate was substituted for2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrroleditrifluoroacetate: ¹H NMR (400 MHz, CDCl₃) δ8.03 (d, J=5.4 Hz, 1H),6.07-5.97 (m, 2H), 4.38 (m, 1H), 3.91 (s, 4H), 3.28 (s, 4H), 2.55-2.41(m, 2H), 2.34 (s, 3H), 2.30 (dd, J=6.2, 12.8 Hz, 1H), 1.82-1.45 (m, 9H),1.45-1.37 (m, 1H), 1.37-1.07 (m, 3H); MS (LC/MS, M+H⁺): m/z 370.2.

Example 92: Preparation of3-(2-(6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one,except 2-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptaneditrifluoroacetate was substituted for2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrroleditrifluoroacetate. A third purification was need via columnchromatography on a C18 column. (acetonitrile/H₂O, 0%˜100%, w/0.1%HCOOH): ¹H NMR (400 MHz, CDCl₃) δ5.97 (s, 2H), 4.45 (m, 1H), 4.21 (s,4H), 3.55 (s, 4H), 2.70 (m, 2H), 2.57 (s, 6H), 2.40 (dd, J=6.2, 12.7 Hz,1H), 1.91-1.54 (m, 9H), 1.54-1.45 (m, 1H), 1.45-1.13 (m, 3H); MS (LC/MS,M+H⁺): m/z 384.2.

Example 93: Preparation of3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:A mixture of 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one (0.075g, 0.301 mmol, 1 eq.), acetonitrile (3 mL),2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole (0.073 g, 0.361 mmol, 1.2 eq.)and N,N-diisopropylethyl amine (0.116 g, 0.903 mmol, 3 eq.) wasmicrowaved at 120° C. for 4 hrs. The resulting solution was concentratedin vacuo to give a crude residue that was first purified by columnchromatography (methanol/dichloromethane, 0%˜10%). ¹H NMR (400 MHz,CDCl₃) δ7.15 (m, 2H), 6.96 (m, 2H), 4.50 (m, 1H), 3.08-2.92 (m, 6H),2.86 (b, 2H), 2.60 (t, J=6.9 Hz, 2H), 2.37-2.24 (m, 5H), 2.14 (dd,J=6.7, 13.0 Hz, 1H), 1.99-1.75 (m, 3H), 1.64 (m, 4H), 0.94 (dt, J=7.4,18.1 Hz, 6H); MS (LC/MS, M+H⁺): m/z 371.2.

Example 94: Preparation of3,3-diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃) δ7.13(t, J=8.0 Hz, 1H), 6.58 (d, J=7.4 Hz, 1H), 6.53-6.45 (m, 2H), 4.47 (m,1H), 3.37 (m, 2H), 3.18 (dt, J=2.8, 9.4 Hz, 2H), 2.95 (b, 2H), 2.86 (m,2H), 2.59 (t, J=7.0 Hz, 2H), 2.41 (dd, J=4.0, 8.9 Hz, 2H), 2.33 (s, 3H),2.12 (dd, J=6.6, 13.0 Hz, 1H), 1.97-1.73 (m, 3H), 1.62 (q, J=7.5 Hz,4H), 0.92 (dt, J=7.5, 14.8 Hz, 6H); MS (LC/MS, M+H⁺): m/z 371.2.

Example 95: Preparation of3,3-diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(p-tolyl)octahydropyrrolo[3,4-c]pyrrole was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃) δ6.89(d, J=8.4 Hz, 2H), 6.45 (d, J=8.4 Hz, 2H), 4.32 (m, 1H), 3.17 (m, 2H),2.99 (dt, J=3.0, 9.2 Hz, 2H), 2.78 (b, 2H), 2.70 (m, 2H), 2.42 (t, J=6.9Hz, 2H), 2.42 (dd, J=4.0, 8.8 Hz, 2H), 2.11 (s, 3H), 2.97 (dd, J=6.8,13.0 Hz, 1H), 1.81-1.57 (m, 3H), 1.45 (q, J=7.2 Hz, 4H), 0.76 (dt,J=7.5, 14.7 Hz, 6H); MS (LC/MS, M+H⁺): m/z 371.2.

Example 96: Preparation of2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrilehydrochloride was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃) δ7.45(dd, J=1.5, 7.6 Hz, 1H), 7.36 (m, 1H), 6.81-6.68 (m, 2H), 4.45 (m, 1H),3.62 (m, 2H), 3.45 (td, J=2.0, 8.6 Hz, 2H), 2.92 (b, 2H), 2.74 (m, 2H),2.63-2.53 (m, 2H), 2.52-2.46 (m, 2H), 2.11 (dd, J=6.8, 13.0 Hz, 1H),1.94-1.70 (m, 3H), 1.58 (qd, J=2.6, 7.4 Hz, 4H), 0.88 (dt, J=7.3, 14.8Hz, 6H); MS (LC/MS, M+H⁺): m/z 382.2.

Example 97: Preparation of3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile wassubstituted for 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400MHz, CDCl₃) δ7.26 (m, 1H), 6.95 (d, J=7.5 Hz, 1H), 6.82-6.75 (m, 2H),4.44 (m, 1H), 3.44 (t, J=8.7 Hz, 2H), 3.15 (dt, J=3.8, 9.4 Hz, 2H), 2.98(b, 2H), 2.73 (m, 2H), 2.57 (t, J=7.0 Hz, 2H), 2.50 (dd, J=3.1, 9.1 Hz,2H), 2.10 (dd, J=6.8, 12.9 Hz, 1H), 1.94-1.70 (m, 3H), 1.59 (q, J=7.3Hz, 4H), 0.89 (dt, J=5.4, 14.9 Hz, 6H); MS (LC/MS, M+H⁺): m/z 382.2.

Example 98: Preparation of4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile wassubstituted for 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400MHz, CDCl₃) δ7.44 (d, J=8.9 Hz, 2H), 6.54 (d, J=8.7 Hz, 2H), 4.44 (m,1H), 3.55 (t, J=9.0 Hz, 2H), 3.23 (dt, J=3.6, 9.9 Hz, 2H), 3.00 (b, 2H),2.72 (m, 2H), 2.64-2.50 (m, 4H), 2.10 (dd, J=6.7, 13.1 Hz, 1H),1.94-1.71 (m, 3H), 1.59 (q, J=7.5 Hz, 4H), 0.89 (dt, J=5.1, 14.9 Hz,6H); MS (LC/MS, M+H⁺): m/z 382.2.

Example 99: Preparation of3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(2-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole was substitutedfor 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ6.83-6.61 (m, 4H), 4.34 (m, 1H), 3.71 (s, 3H), 3.23 (q, J=7.5 Hz, 2H),2.86 (m, 2H), 2.72 (b, 2H), 2.58 (b, 2H), 2.44 (m, 2H), 2.31 (dt, J=3.2,8.8 Hz, 2H), 1.98 (dd, J=6.8, 13.1 Hz, 1H), 1.84-1.73 (m, 1H), 1.73-1.58(m, 2H), 1.47 (qd, J=1.5, 7.5 Hz, 4H), 0.77 (dt, J=7.3, 15.8 Hz, 6H); MS(LC/MS, M+H⁺): m/z 387.2.

Example 100: Preparation of3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: The title compoundwas prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(3-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole was substitutedfor 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ7.14 (t, J=8.2 Hz, 1H), 6.30 (m, 2H), 6.20 (t, J=2.2 Hz, 1H), 4.46 (m,1H), 3.79 (s, 3H), 3.38 (t, J=8.2 Hz, 2H), 3.17 (dt, J=3.0, 9.5 Hz, 2H),2.94 (b, 2H), 2.86-2.77 (m, 2H), 2.57 (t, J=7.1 Hz, 2H), 2.42 (dd,J=3.9, 9.0 Hz, 2H), 2.11 (dd, J=6.8, 13.0 Hz, 1H), 1.95-1.72 (m, 3H),1.61 (qd, J=1.5, 7.5 Hz, 4H), 0.91 (dt, J=7.4, 14.8 Hz, 6H); MS (LC/MS,M+H⁺): m/z 387.2.

Example 101: Preparation of3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: The title compoundwas prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(4-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole was substitutedfor 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ6.83 (d, J=9.0 Hz, 2H), 6.65 (d, J=9.0 Hz, 2H), 4.46 (m, 1H), 3.76 (s,3H), 3.28 (m, 2H), 3.10 (dt, J=3.2, 9.1 Hz, 2H), 2.92 (b, 2H), 2.84 (b,2H), 2.63-2.51 (m, 2H), 2.39 (dd, J=4.0, 8.7 Hz, 2H), 2.11 (dd, J=6.8,13.0 Hz, 1H), 1.97-1.71 (m, 3H), 1.61 (qd, J=1.3, 7.4 Hz, 4H), 0.91 (dt,J=7.3, 14.8 Hz, 6H); MS (LC/MS, M+H⁺): m/z 387.2.

Example 102: Preparation of3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: The title compoundwas prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 4-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)morpholinehydrochloride was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ7.05-6.94 (m, 3H), 6.91-6.83 (m, 1H), 4.49 (m, 1H) 3.85 (t, J=4.7 Hz,4H), 3.68-3.42 (m, 4H), 3.22-2.84 (m, 10H), 2.61 (b, 2H), 2.30 (b, 1H),2.19 (dd, J=6.7, 13.2 Hz, 1H), 2.05-1.90 (m, 1H), 1.84 (dd, J=9.3, 13.2Hz, 1H), 1.67-1.56 (m, 4H), 0.91 (dt, J=7.3, 16.5 Hz, 6H); MS (LC/MS,M+H⁺): m/z 442.2.

Example 103: Preparation of5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(2-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrolehydrochloride was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ7.46-7.29 (m, 5H), 7.01-6.86 (m, 3H), 6.81 (dd, J=1.4, 7.7 Hz, 1H),5.03 (s, 2H), 4.43 (m, 1H), 3.61 (b, 2H), 3.36 (t, J=10.6 Hz, 2H),3.17-2.97 (m, 3H), 2.91 (td, J=5.3, 12.2 Hz, 1H), 2.86-2.73 (m, 2H),2.58-2.37 (m, 2H), 2.30 (m, 1H), 2.17 (dd, J=6.7, 13.1 Hz, 1H),1.92-1.73 (m, 2H), 1.61 (q, J=7.4 Hz, 4H), 0.91 (dt, J=7.0, 13.9 Hz,6H); MS (LC/MS, M+H⁺): m/z 463.2.

Example 104: Preparation of5-(2-(5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(3-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrolehydrochloride was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ7.39-7.33 (m, 2H), 7.33-7.26 (m, 2H), 7.26-7.20 (m, 1H), 7.05 (m, 1H),6.29 (dd, J=1.7, 8.1 Hz, 1H), 6.24-6.18 (m, 2H), 4.96 (s, 2H), 4.37 (m,1H), 3.28 (m, 2H), 3.08 (dt, J=2.9, 9.3 Hz, 2H), 2.93-2.81 (m, 2H),2.81-2.69 (m, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.33 (dd, J 3.9, 8.9 Hz, 2H),2.02 (dd, J=6.7, 13.0 Hz, 1H), 1.87-1.63 (m, 3H), 1.52 (qd, J=1.2, 7.4Hz, 4H), 0.82 (dt, J=7.4, 14.9 Hz, 6H); MS (LC/MS, M+H⁺): m/z 463.2.

Example 105: Preparation of5-(2-(5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(4-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrolehydrochloride was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ7.37-7.31 (m, 2H), 7.31-7.25 (m, 2H), 7.24-7.18 (m, 1H), 6.81 (d, J=9.0Hz, 2H), 6.55 (d, J=9.0 Hz, 2H), 4.92 (s, 2H), 4.37 (m, 1H), 3.19 (m,2H), 3.01 (dt, J=3.1, 9.3 Hz, 2H), 2.89-2.80 (m, 2H), 2.80-2.70 (m, 2H),2.48 (t, J=6.9 Hz, 2H), 2.29 (dd, J 3.9, 8.6 Hz, 2H), 2.02 (dd, J=6.7,13.1 Hz, 1H), 1.87-1.62 (m, 3H), 1.52 (q, J=7.3 Hz, 4H), 0.82 (dt,J=7.5, 14.5 Hz, 6H); MS (LC/MS, M+H⁺): m/z 463.2.

Example 106: Preparation of3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: To a dry roundbottom flask, 0.013 g of 10% Pd/C (20% wt) was added and wet with asmall amount of ethyl acetate. Following, a solution of5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one(0.065 g, 0.140 mmol, 1 eq.) in MeOH (1.5 mL) was added slowly to thePd/C containing round bottom flask. This system was then flushed 3× withH₂, using a balloon filled with H₂. The reaction was allowed to stirunder 1 atm H₂ for overnight at room temperature. The Pd/C was removedvia filtration through a plug of Celite. The filtrate was concentratedin vacuo to give a crude residue that was first purified by columnchromatography (methanol/dichloromethane, 0%˜10%). ¹H NMR (400 MHz,CDCl₃) δ7.13 (dd, J=1.3, 7.8 Hz, 1H), 7.05 (td, J=1.3, 7.7 Hz, 1H), 6.93(dd, J=1.3, 8.1 Hz, 1H), 6.85 (td, J=1.4, 7.7 Hz, 1H), 4.52 (m, 1H),3.12-3.00 (m, 2H), 2.98-2.74 (m, 6H), 2.65 (t, J=7.3 Hz, 2H), 2.58-2.46(m, 2H), 2.16 (dd, J=6.7, 13.1 Hz, 1H), 2.00-1.76 (m, 3H), 1.64 (q,J=7.5 Hz, 4H), 0.95 (dt, J=7.4, 22.8 Hz, 6H); MS (LC/MS, M+H⁺): m/z373.2.

Example 107: Preparation of3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: The title compoundwas prepared according to the procedure for3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 5-(2-(5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-onewas substituted for5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one:¹H NMR (400 MHz, CDCl₃) δ6.85 (t, J=8.1 Hz, 1H), 6.00 (td, J=1.8, 7.6Hz, 2H), 5.91 (t, J=2.3 Hz, 1H), 4.24 (m, 1H), 3.18-3.05 (m, 2H), 2.97(d, J=9.2 Hz, 2H), 2.83-2.64 (m, 4H), 2.44 (t, J=7.3 Hz, 2H), 2.25 (m,2H), 1.91 (dd, J=6.7, 13.1 Hz, 1H), 1.77-1.53 (m, 3H), 1.40 (q, J=7.4Hz, 4H), 0.70 (dt, J=7.4, 15.6 Hz, 6H); MS (LC/MS, M+H⁺): m/z 373.2.

Example 108: Preparation of3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-onetrifluoroacetate: The title compound was prepared according to theprocedure for3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except5-(2-(5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-onewas substituted for5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-oneand the reaction time was extended to 3 days. A second purification wasneed via column chromatography on a C18 column. (acetonitrile/H₂O,0%-100%, w/0.1% TFA): ¹H NMR (400 MHz, MeOD) δ6.78-6.67 (m, 4H), 4.54(m, 1H), 3.69 (b, 2H), 3.45 (dd, J=7.2, 9.6 Hz, 2H), 3.40-3.09 (m, 6H),2.98 (m, 2H), 2.28 (dd, J=6.7, 13.2 Hz, 1H), 2.20-1.97 (m, 2H), 1.91(dd, J=9.4, 13.2 Hz, 1H), 1.74-1.52 (m, 4H), 0.94 (dt, J=5.0, 14.9 Hz,6H); MS (LC/MS, M+H⁺): m/z 373.2.

Example 109: Preparation of3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one,except 2-phenyloctahydropyrrolo[3,4-c]pyrrole dihydrochloride wassubstituted for 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate: ¹HNMR (400 MHz, CDCl₃) δ7.14 (m, 2H), 6.64 (t, J=7.2 Hz, 1H), 6.57 (d,J=8.5 Hz, 2H), 4.37 (m, 1H), 3.29 (t, J=8.1 Hz, 2H), 3.08 (dt, J=2.7,9.3 Hz, 2H), 2.92-2.79 (b, 2H), 2.78-2.65 (m, 2H), 2.47 (t, J=6.9 Hz,2H), 2.32 (dd, J=4.0, 8.9 Hz, 2H), 2.02 (dd, J=6.7, 13.1 Hz, 1H),1.87-1.61 (m, 3H), 1.51 (q, J=7.3 Hz, 4H), 0.81 (dt, J=7.5, 13.9 Hz,6H); MS (LC/MS, M+H⁺): m/z 357.2

Formulations

The present invention also relates to compositions or formulations whichcomprise the sigma-2 receptor binders and sigma-2 receptor activitymodulators according to the present invention. In general, thecompositions of the present invention comprise an effective amount ofone or more compounds of the disclosure and salts thereof according tothe present invention which are effective for providing modulation ofsigma-2 receptor activity; and one or more excipients.

For the purposes of the present invention the term “excipient” and“carrier” are used interchangeably throughout the description of thepresent invention and said terms are defined herein as, “ingredientswhich are used in the practice of formulating a safe and effectivepharmaceutical composition.”

The formulator will understand that excipients are used primarily toserve in delivering a safe, stable, and functional pharmaceutical,serving not only as part of the overall vehicle for delivery but also asa means for achieving effective absorption by the recipient of theactive ingredient. An excipient may fill a role as simple and direct asbeing an inert filler, or an excipient as used herein may be part of apH stabilizing system or coating to insure delivery of the ingredientssafely to the stomach. The formulator can also take advantage of thefact the compounds of the present invention have improved cellularpotency, pharmacokinetic properties, as well as improved oralbioavailability.

The present teachings also provide pharmaceutical compositions thatinclude at least one compound described herein and one or morepharmaceutically acceptable carriers, excipients, or diluents. Examplesof such carriers are well known to those skilled in the art and can beprepared in accordance with acceptable pharmaceutical procedures, suchas, for example, those described in Remington's Pharmaceutical Sciences,17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton,Pa. (1985), the entire disclosure of which is incorporated by referenceherein for all purposes. As used herein, “pharmaceutically acceptable”refers to a substance that is acceptable for use in pharmaceuticalapplications from a toxicological perspective and does not adverselyinteract with the active ingredient. Accordingly, pharmaceuticallyacceptable carriers are those that are compatible with the otheringredients in the formulation and are biologically acceptable.Supplementary active ingredients can also be incorporated into thepharmaceutical compositions.

Compounds of the present teachings can be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich can also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents, or encapsulating materials. The compoundscan be formulated in conventional manner, for example, in a mannersimilar to that used for known sigma-2 receptor activity modulators.Oral formulations containing a compound disclosed herein can compriseany conventionally used oral form, including tablets, capsules, buccalforms, troches, lozenges and oral liquids, suspensions or solutions. Inpowders, the carrier can be a finely divided solid, which is anadmixture with a finely divided compound. In tablets, a compounddisclosed herein can be mixed with a carrier having the necessarycompression properties in suitable proportions and compacted in theshape and size desired. The powders and tablets can contain up to 99% ofthe compound.

Capsules can contain mixtures of one or more compound(s) disclosedherein with inert filler(s) and/or diluent(s) such as pharmaceuticallyacceptable starches (e.g., corn, potato or tapioca starch), sugars,artificial sweetening agents, powdered celluloses (e.g., crystalline andmicrocrystalline celluloses), flours, gelatins, gums, and the like.

Useful tablet formulations can be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants, surfacemodifying agents (including surfactants), suspending or stabilizingagents, including, but not limited to, magnesium stearate, stearic acid,sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, microcrystalline cellulose, sodiumcarboxymethyl cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodiumcitrate, complex silicates, calcium carbonate, glycine, sucrose,sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin,mannitol, sodium chloride, low melting waxes, and ion exchange resins.Surface modifying agents include nonionic and anionic surface modifyingagents. Representative examples of surface modifying agents include, butare not limited to, poloxamer 188, benzalkonium chloride, calciumstearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitanesters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate,magnesium aluminum silicate, and triethanolamine. Oral formulationsherein can utilize standard delay or time-release formulations to alterthe absorption of the compound(s). The oral formulation can also consistof administering a compound disclosed herein in water or fruit juice,containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions,emulsions, syrups, elixirs, and for inhaled delivery. A compound of thepresent teachings can be dissolved or suspended in a pharmaceuticallyacceptable liquid carrier such as water, an organic solvent, or amixture of both, or a pharmaceutically acceptable oils or fats. Theliquid carrier can contain other suitable pharmaceutical additives suchas solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers, and osmo-regulators. Examples ofliquid carriers for oral and parenteral administration include, but arenot limited to, water (particularly containing additives as describedherein, e.g., cellulose derivatives such as a sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols andpolyhydric alcohols, e.g., glycols) and their derivatives, and oils(e.g., fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can be an oily ester such as ethyl oleateand isopropyl myristate. Sterile liquid carriers are used in sterileliquid form compositions for parenteral administration. The liquidcarrier for pressurized compositions can be halogenated hydrocarbon orother pharmaceutically acceptable propellants.

Liquid pharmaceutical compositions, which are sterile solutions orsuspensions, can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Compositions for oral administration can bein either liquid or solid form.

Preferably the pharmaceutical composition is in unit dosage form, forexample, as tablets, capsules, powders, solutions, suspensions,emulsions, granules, or suppositories. In such form, the pharmaceuticalcomposition can be sub-divided in unit dose(s) containing appropriatequantities of the compound. The unit dosage forms can be packagedcompositions, for example, packeted powders, vials, ampoules, prefilledsyringes or sachets containing liquids. Alternatively, the unit dosageform can be a capsule or tablet itself, or it can be the appropriatenumber of any such compositions in package form. Such unit dosage formcan contain from about 1 mg/kg of compound to about 500 mg/kg ofcompound, and can be given in a single dose or in two or more doses.Such doses can be administered in any manner useful in directing thecompound(s) to the recipient's bloodstream, including orally, viaimplants, parenterally (including intravenous, intraperitoneal andsubcutaneous injections), rectally, vaginally, and transdermally.

When administered for the treatment or inhibition of a particulardisease state or disorder, it is understood that an effective dosage canvary depending upon the particular compound utilized, the mode ofadministration, and severity of the condition being treated, as well asthe various physical factors related to the individual being treated. Intherapeutic applications, a compound of the present teachings can beprovided to a patient already suffering from a disease in an amountsufficient to cure or at least partially ameliorate the symptoms of thedisease and its complications. The dosage to be used in the treatment ofa specific individual typically must be subjectively determined by theattending physician. The variables involved include the specificcondition and its state as well as the size, age and response pattern ofthe patient.

In some cases it may be desirable to administer a compound directly tothe airways of the patient, using devices such as, but not limited to,metered dose inhalers, breath-operated inhalers, multidose dry-powderinhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosoldispensers, and aerosol nebulizers. For administration by intranasal orintrabronchial inhalation, the compounds of the present teachings can beformulated into a liquid composition, a solid composition, or an aerosolcomposition. The liquid composition can include, by way of illustration,one or more compounds of the present teachings dissolved, partiallydissolved, or suspended in one or more pharmaceutically acceptablesolvents and can be administered by, for example, a pump or asqueeze-actuated nebulized spray dispenser. The solvents can be, forexample, isotonic saline or bacteriostatic water. The solid compositioncan be, by way of illustration, a powder preparation including one ormore compounds of the present teachings intermixed with lactose or otherinert powders that are acceptable for intrabronchial use, and can beadministered by, for example, an aerosol dispenser or a device thatbreaks or punctures a capsule encasing the solid composition anddelivers the solid composition for inhalation. The aerosol compositioncan include, by way of illustration, one or more compounds of thepresent teachings, propellants, surfactants, and co-solvents, and can beadministered by, for example, a metered device. The propellants can be achlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or otherpropellants that are physiologically and environmentally acceptable.]

Compounds described herein can be administered parenterally orintraperitoneally. Solutions or suspensions of these compounds or apharmaceutically acceptable salts, hydrates, or esters thereof can beprepared in water suitably mixed with a surfactant such ashydroxyl-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, and mixtures thereof in oils. Underordinary conditions of storage and use, these preparations typicallycontain a preservative to inhibit the growth of microorganisms.

The pharmaceutical forms suitable for injection can include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In some embodiments, the form can sterile and its viscositypermits it to flow through a syringe. The form preferably is stableunder the conditions of manufacture and storage and can be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g., glycerol, propylene glycol andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils.

Compounds described herein can be administered transdermally, i.e.,administered across the surface of the body and the inner linings ofbodily passages including epithelial and mucosal tissues. Suchadministration can be carried out using the compounds of the presentteachings including pharmaceutically acceptable salts, hydrates, oresters thereof, in lotions, creams, foams, patches, suspensions,solutions, and suppositories (rectal and vaginal).

Transdermal administration can be accomplished through the use of atransdermal patch containing a compound, such as a compound disclosedherein, and a carrier that can be inert to the compound, can benon-toxic to the skin, and can allow delivery of the compound forsystemic absorption into the blood stream via the skin. The carrier cantake any number of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments can be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the compound can also be suitable. Avariety of occlusive devices can be used to release the compound intothe blood stream, such as a semi-permeable membrane covering a reservoircontaining the compound with or without a carrier, or a matrixcontaining the compound. Other occlusive devices are known in theliterature.

Compounds described herein can be administered rectally or vaginally inthe form of a conventional suppository. Suppository formulations can bemade from traditional materials, including cocoa butter, with or withoutthe addition of waxes to alter the suppository's melting point, andglycerin. Water-soluble suppository bases, such as polyethylene glycolsof various molecular weights, can also be used.

Lipid formulations or nanocapsules can be used to introduce compounds ofthe present teachings into host cells either in vitro or in vivo. Lipidformulations and nanocapsules can be prepared by methods known in theart.

To increase the effectiveness of compounds of the present teachings, itcan be desirable to combine a compound with other agents effective inthe treatment of the target disease. For example, other active compounds(i.e., other active ingredients or agents) effective in treating thetarget disease can be administered with compounds of the presentteachings. The other agents can be administered at the same time or atdifferent times than the compounds disclosed herein.

Compounds of the present teachings can be useful for the treatment orinhibition of a pathological condition or disorder in a mammal, forexample, a human subject. The present teachings accordingly providemethods of treating or inhibiting a pathological condition or disorderby providing to a mammal a compound of the present teachings includingits pharmaceutically acceptable salt) or a pharmaceutical compositionthat includes one or more compounds of the present teachings incombination or association with pharmaceutically acceptable carriers.Compounds of the present teachings can be administered alone or incombination with other therapeutically effective compounds or therapiesfor the treatment or inhibition of the pathological condition ordisorder.

Non-limiting examples of compositions according to the present inventioninclude from about 0.001 mg to about 1000 mg of one or more compounds ofthe disclosure according to the present invention and one or moreexcipients; from about 0.01 mg to about 100 mg of one or more compoundsof the disclosure according to the present invention and one or moreexcipients; and from about 0.1 mg to about 10 mg of one or morecompounds of the disclosure according to the present invention; and oneor more excipients.

Procedures

The following procedure may be utilized in evaluating and selectingcompounds as sigma-2 receptor binders and sigma-2 receptor activitymodulators.

Radiolabel Binding Studies for the sigma-2 receptor:

A solution of the compound of the disclosure to be tested is prepared asa 1-mg/ml stock in Assay Buffer or DMSO according to its solubility. Asimilar stock of the reference compound Haloperidol is also prepared asa positive control. Eleven dilutions (5× assay concentration) of thecompound of the disclosure and Haloperidol are prepared in the AssayBuffer by serial dilution to yield final corresponding assayconcentrations ranging from 10 pM to 10 μM.

A stock concentration of 5 nM ³H-1,3-di-(2-tolyl)guanidine (³H-DTG) isprepared in 50 mM Tris-HCl, 10 mM MgCl₂, 1 mM EDTA, pH 7.4 (AssayBuffer). Aliquots (50 μl) of radioligand are dispensed into the wells ofa 96-well plate containing 100 μl of Assay Buffer. Duplicate 50-μlaliquots of the compound of the disclosure test and Haloperidol positivecontrol reference compound serial dilutions are added.

Membrane fractions of cells expressing recombinant sigma-2 receptors (50μL) are dispensed into each well. The membranes are prepared from stablytransfected cell lines expressing sigma-2 receptors cultured on 10-cmplates by harvesting PBS-rinsed monolayers, resuspending and lysing inchilled, hypotonic 50 mM Tris-HCl, pH 7.4, centrifuging at 20,000×g,decanting the supernatant and storing at −80° C.; the membranepreparations are resuspended in 3 ml of chilled Assay Buffer andhomogenized by several passages through a 26 gauge needle before usingin the assay.

The 250-μl reactions are incubated at room temperature for 1.5 hours,then harvested by rapid filtration onto 0.3% polyethyleneimine-treated,96-well filter mats using a 96-well Filtermate harvester. Four rapid500-μl washes are performed with chilled Assay Buffer to reducenon-specific binding. The filter mats are dried, then scintillant isadded to the filters and the radioactivity retained on the filters iscounted in a Microbeta scintillation counter.

Raw data (dpm) representing total radioligand binding (i.e.,specific+non-specific binding) are plotted as a function of thelogarithm of the molar concentration of the competitor (i.e., test orreference compound). Non-linear regression of the normalized (i.e.,percent radioligand binding compared to that observed in the absence oftest or reference compound) raw data is performed in Prism 4.0 (GraphPadSoftware) using the built-in three parameter logistic model describingligand competition binding to radioligand-labeled sites:

y=bottom+[(top−bottom)/(1+10x−log IC ₅₀)]

where bottom equals the residual radioligand binding measured in thepresence of 10 μM reference compound (i.e., non-specific binding) andtop equals the total radioligand binding observed in the absence ofcompetitor. The log IC₅₀ (i.e., the log of the ligand concentration thatreduces radioligand binding by 50%) is thus estimated from the data andused to obtain the Ki by applying the Cheng-Prusoff approximation:

Ki=IC ₅₀/(1+[ligand]/KD)

where [ligand] equals the assay radioligand concentration and KD equalsthe affinity constant of the radioligand for the target receptor.

Compounds of the disclosure are also screened at a single concentrationof 10 μM using the same method described for the Radiolabel BindingStudies for sigma-2 receptors to determine the percent inhibition of³H-DTG binding.

Results for representative compounds according to the present inventionare listed in Table 21.

TABLE 21 Radiolabel Binding Studies for the sigma-2 receptors resultsfor exemplary compounds of the disclosure Entry Structure Sigma-2 IC₅₀(nm) 1

3.5 2

29 3

39 4

2.0 5

2.4 6

3.9 7

11 8

24 9

34 10

59 11

30 12

3.9 13

1.2 14

1.5 15

53 16

6.8 17

7.0 18

9.6 19

6.5 20

25 21

22

1.-20. (canceled)
 21. A compound having formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein: R^(1a) andR^(1b) are each independently selected from the group consisting ofhydrogen, C₁₋₆ linear alkyl, and C₁-6 branched alkyl, R^(1a) and R^(1b)may be taken together with the atom to which they are bound to form acyclohexyl; and R³ is optionally substituted phenyl or optionallysubstituted pyridyl;
 22. The compound of claim 21, wherein R^(1a) andR^(1b) are each independently C₁₋₆ linear alkyl or C₁₋₆ branched alkyl.23. The compound of claim 22, wherein R^(1a) and R^(1b) are eachindependently methyl or ethyl.
 24. The compound of claim 21, wherein R³is selected from a group consisting of phenyl, 4-OH-phenyl, 3-OH-phenyl,2-OH-phenyl, 4-CH₃-phenyl, 3-CH₃-phenyl, 2-CH₃-phenyl, 4-OCH₃-phenyl,3-OCH₃-phenyl, 2-OCH₃-phenyl, 4-CN-phenyl, 3-CN-phenyl, 2-CN-phenyl,4-F-phenyl, 3-F-phenyl, 2-F-phenyl, 4-Cl-phenyl, 3-Cl-phenyl,2-Cl-phenyl, 4-OCF₃-phenyl, 3-OCF₃-phenyl, 2-OCF₃-phenyl,4-isopropyl-phenyl, 3-isopropyl-phenyl, 2-isopropyl-phenyl,4-cyclopropyl-phenyl, 3-cyclopropyl-phenyl, 2-cyclopropyl-phenyl,4-morpholino-phenyl, 3-morpholino-phenyl, 2-morpholino-phenyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-CH₃-4-pyridyl, 3-CH₃-4-pyridyl,3,5-dimethylpyridin-4-yl, 2,6-dimethylpyridin-4-yl, 2-CF₃-phenyl,3-CF₃-phenyl, 4-CF₃-phenyl, 2-NH2-phenyl, 3-NH2-phenyl, 4-NH2-phenyl,2-tBu-phenyl, 3-tBu-phenyl, 4-tBu-phenyl, 2-NO₂-phenyl, 3-NO₂-phenyl,4-NO₂-phenyl, 2-SCH₃-phenyl, 3-SCH₃-phenyl, 4-SCH₃-phenyl,2-SO₂CH₃-phenyl, 3-SO₂CH₃-phenyl, 4-SO₂CH₃-phenyl, 2-SO₂NH2-phenyl,3-SO₂NH2-phenyl, 4-SO₂NH2-phenyl, 2-CO₂NH2-phenyl, 3-CO₂NH2-phenyl,4-CO₂NH2-phenyl, 2-Br-phenyl, 3-Br-phenyl, 4-Br-phenyl,2,3-di-CH₃-phenyl, 2,4-di-CH₃-phenyl, 2,5-di-CH₃-phenyl,2,6-di-CH₃-phenyl, 3,4-di-CH₃-phenyl, 3,5-di-CH₃-phenyl,2,3-di-Cl-phenyl, 2,4-di-Cl-phenyl, 2,5-di-Cl-phenyl, 2,6-di-Cl-phenyl,3,4-di-Cl-phenyl, 3,5-di-Cl-phenyl, 2-morpholino-4-CH₃-phenyl,2-morpholino-4-CN-phenyl, 2-morpholino-4-OH-phenyl,2,3-dimethylpyridin-4-yl, and 3,6-dimethylpyridin-4-yl.
 25. The compoundof claim 24, wherein R³ is unsubstituted phenyl, 4-pyridyl,3-CH₃-4-pyridyl, 2-CH₃-4-pyridyl, or 2,6-dimethylpyridin-4-yl.
 26. Thecompound of claim 21, wherein the compound is selected from a groupconsisting of

or a pharmaceutically acceptable salt thereof.
 27. A method for treatinga disease that involve dysregulation of sigma-2 receptor activity saidmethod comprising administering to a subject an effective amount of atleast one compound according to claim 21 to treat the disease.
 28. Themethod of claim 27, wherein the at least one compound is administered ina composition further comprising at least one excipient.
 29. The methodof claim 27, wherein the disease that involves dysregulation of sigma-2receptor activity is selected from the group consisting of generalizedanxiety disorder, social anxiety disorder, panic disorder, agoraphobia,obsessive-compulsive disorder post-traumatic stress disorder,depression, bipolar disorder, anorexia nervosa, bulimia nervosa, asubstance use disorder, schizophrenia, Alzheimer's disease, mildcognitive impairment, a memory disorder, and cancer.
 30. The method ofclaim 29, wherein the cancer is selected from the group consisting ofpancreatic cancer, lung cancer, breast cancer, melanoma, prostatecancer, and ovarian cancer.